What is rhabdomyosarcoma

Rhabdomyosarcoma is a cancer that starts in skeletal muscles. Rhabdomyosarcoma can occur in children or adults. Skeletal (voluntary) muscles are muscles that you control to move parts of your body. Skeletal muscle is under voluntary control and is the major muscle component of your body. Skeletal muscle is responsible for the maintenance of body posture and also for the gross and fine movements of the limbs. In addition, the skeletal muscle of the eye (the extraocular muscles) are responsible for eye movements; and the visceral striated muscle is responsible for important elements of speech, breathing and swallowing.

About 3% of all childhood cancers are rhabdomyosarcoma. Childhood rhabdomyosarcoma is a soft tissue malignant tumor of mesenchymal origin. More than 70% of malignant mesenchymal tumors are rhabdomyosarcomas and occurs with highest incidence in children and adolescents. Rhabdomyosarcoma accounts for approximately 3.5% of the cases of cancer among children aged 0 to 14 years and 2% of the cases among adolescents and young adults aged 15 to 19 years ¹⁾. The median age at presentation is 5 years. Rhabdomyosarcoma is slightly more common in boys than in girls. No particular race or ethnic group seems to have an unusually high rate of rhabdomyosarcoma. The incidence is 4.5 cases per 1 million children, which translates into about 350 new cases of rhabdomyosarcoma occur each year in the United States ²⁾. Fifty percent of these cases are seen in the first decade of life ³⁾. Males have a higher incidence of embryonal tumors, and blacks have a slightly higher incidence of alveolar tumors ⁴⁾. The number of new cases has not changed much over the past few decades.

Incidence may depend on the histologic subtype of rhabdomyosarcoma, as follows:

1. Embryonal: Patients with embryonal rhabdomyosarcoma are predominantly male (male to female ratio, 1.5). The peak incidence is in the 0- to 4-year age group, with approximately 4 cases per 1 million children, with a lower rate in adolescents, approximately 1.5 cases per 1 million adolescents. This subtype constitutes 57% of patients in the Surveillance, Epidemiology, and End Results (SEER) database ⁵⁾.
2. Alveolar: The incidence of alveolar rhabdomyosarcoma does not vary by sex and is constant from ages 0 to 19 years, with approximately 1 case per 1 million children and adolescents. This subtype constitutes 23% of patients in the SEER database ⁶⁾.
3. Other: Pleomorphic/anaplastic, mixed type, and spindle cell subtypes each constitute less than 2% of children with rhabdomyosarcoma ⁷⁾.

The following are the most common primary sites for rhabdomyosarcoma ⁸⁾:

• Head and neck region (parameningeal) (approximately 25%).
• Genitourinary tract (approximately 31%).
• Extremities (approximately 13%). Within extremity tumors, tumors of the hand and foot occur more often in older patients and have an alveolar histology ⁹⁾.

Other less common primary sites include the trunk, chest wall, perineal/anal region, and abdomen, including the retroperitoneum and biliary tract ¹⁰⁾.

There are 3 distinct types of rhabdomyosarcoma:

1. Embryonal rhabdomyosarcoma
2. Alveolar rhabdomyosarcoma
3. Anaplastic rhabdomyosarcoma and undifferentiated sarcoma (formerly called pleomorphic rhabdomyosarcoma)

The response to treatment varies according to the type of rhabdomyosarcoma cancer you have.

About 7 weeks into the development of an embryo, cells called rhabdomyoblasts (which will eventually form skeletal muscles) begin to form. These are the cells that can develop into rhabdomyosarcoma. Because rhabdomyosarcoma is a cancer of embryonal cells, it is much more common in children, although it does sometimes occur in adults.

You might think of your skeletal muscles as being mainly in our arms and legs, but these skeletal muscle cancers can start nearly anywhere in your body, even in some parts of the body that don’t normally have skeletal muscle.

Common sites of rhabdomyosarcoma include:

• Head and neck (such as near the eye, inside the nasal sinuses or throat, or near the spine in the neck)
• Urinary and reproductive organs (bladder, prostate gland, or any of the female organs)
• Arms and legs
• Trunk (chest and abdomen)

Most rhabdomyosarcomas are diagnosed in children and teens, with more than half of them in children younger than 10 years old. These tumors are usually embryonal rhabdomyosarcomas and tend to develop in the head and neck area or in the genital and urinary tracts. Alveolar rhabdomyosarcoma affects all age groups and is found more often in the arms, legs, or trunk.

It is important to realize that the treatment of rhabdomyosarcoma is a very complicated process. Younger patients may suffer long-term consequences of treatments to rhabdomyosarcoma cancer.

Treatment of rhabdomyosarcoma varies depending upon the site of the lesion, but revolves around surgical, chemotherapy and radiotherapy techniques. Surgery and radiotherapy are used to establish local control of the tumor. The early dissemination of this tumor has necessitated systemic chemotherapy to prevent the development of metastatic disease, and also to assist in the maintenance of local disease control.

Continual improvements in survival have been achieved for children and adolescents with cancer ¹¹⁾. Between 1975 and 2010, childhood cancer mortality decreased by more than 50% ¹²⁾. For rhabdomyosarcoma, the 5-year survival rate increased over the same time, from 53% to 67% for children younger than 15 years and from 30% to 51% for adolescents aged 15 to 19 years ¹³⁾.

Childhood and adolescent cancer survivors require close monitoring because side effects of cancer and its therapy may persist or develop months or years after treatment.

Embryonal rhabdomyosarcoma

Embryonal rhabdomyosarcoma usually affects children in their first 5 years of life, but it is the most common type of rhabdomyosarcoma at all ages.

The cells of embryonal rhabdomyosarcoma look like the developing muscle cells of a 6- to 8-week-old embryo. Embryonal rhabdomyosarcoma tends to occur in the head and neck area, bladder, vagina, or in or around the prostate and testicles.

Two subtypes of embryonal rhabdomyosarcoma, botryoid and spindle cell rhabdomyosarcomas, tend to have a better prognosis (outlook) than the more common conventional form of embryonal rhabdomyosarcoma.

Alveolar rhabdomyosarcoma

Alveolar rhabdomyosarcoma typically affects all age groups equally. It makes up a larger portion of rhabdomyosarcoma in older children and teens than in younger children (because embryonal rhabdomyosarcoma is less common at older ages).

Alveolar rhabdomyosarcoma most often occurs in large muscles of the trunk, arms, and legs. The cells of alveolar rhabdomyosarcoma look like the normal muscle cells seen in a 10-week-old fetus.

Alveolar rhabdomyosarcoma tends to grow faster than embryonal rhabdomyosarcoma and usually requires more intense treatment.

Anaplastic rhabdomyosarcoma and undifferentiated sarcoma

Anaplastic rhabdomyosarcoma (formerly called pleomorphic rhabdomyosarcoma) is an uncommon type that occurs in adults but is very rare in children.

Some doctors also group undifferentiated sarcomas with the rhabdomyosarcomas. Using lab tests, doctors can tell that these cancers are sarcomas, but the cells don’t have any features that help classify them further.

Both of these uncommon cancers tend to grow quickly and usually require intensive treatment.

Rhabdomyosarcoma in adults

Most rhabdomyosarcomas develop in children, but they can also occur in adults. Adults are more likely to have faster-growing types of rhabdomyosarcoma and to have them in parts of the body that are harder to treat. Because of this, rhabdomyosarcoma in adults is often harder to treat effectively.

What Are the Differences Between Cancers in Adults and Children?

Cancers that develop in children are often different from the types that develop in adults. Childhood cancers are often the result of DNA changes in cells that take place very early in life, sometimes even before birth. Unlike many cancers in adults, childhood cancers are not strongly linked to lifestyle or environmental risk factors.

There are exceptions, but childhood cancers tend to respond better to treatments such as chemotherapy. Children’s bodies also tend to tolerate chemotherapy better than adults’ bodies do. But cancer treatments such as chemotherapy and radiation therapy can have long-term side effects, so children who have had cancer need careful attention for the rest of their lives.

Since the 1960s, most children and teens with cancer have been treated at specialized centers designed for them. These centers offer the advantage of being treated by a team of specialists who know the differences between adult and childhood cancers, as well as the unique needs of children with cancer and their families. This team usually includes pediatric oncologists (childhood cancer doctors), surgeons, radiation oncologists, pathologists, pediatric oncology nurses, and nurse practitioners.

These centers also have psychologists, social workers, child life specialists, nutritionists, rehabilitation and physical therapists, and educators who can support and educate the entire family.

Most children with cancer in the United States are treated at a center that is a member of the Children’s Oncology Group. All of these centers are associated with a university or children’s hospital. As we have learned more about treating childhood cancer, it has become even more important that treatment be given by experts in this area.

When a child or teen is diagnosed with cancer, it affects every family member and nearly every aspect of the family’s life.

Rhabdomyosarcoma prognosis

The prognosis (outlook) for people with rhabdomyosarcoma depends on many factors, including the type of rhabdomyosarcoma, the location and size of the tumor, the results of surgery, and whether the cancer has metastasized (spread). Children aged 1 to 9 tend to have a better outlook than infants or older children or adults.

Before the advent of chemotherapy in the 1970s the outlook for patients with rhabdomyosarcoma was universally poor. A 5 year survival rate was less than 20%. More recently, however, the cure rate for rhabdomyosarcoma has risen to approximately 70% following the introduction of postoperative systemic chemotherapy.

Parameningeal head and neck tumors and intra-abdominal tumors have the worst prognosis, whilst those in the orbit and urogenital tract are associated with a good prognosis. Female patients have a worse prognosis than do males.

Prognostic factors

Rhabdomyosarcoma is usually curable in children with localized disease who receive combined-modality therapy, with more than 70% of patients surviving 5 years after diagnosis ¹⁴⁾. Relapses are uncommon in patients who were alive and event free at 5 years, with a 10-year late-event rate of 9%. Relapses are more common, however, in patients who have unresectable disease in an unfavorable site at diagnosis and in patients who have metastatic disease at diagnosis ¹⁵⁾.

The prognosis for a child or adolescent with rhabdomyosarcoma is related to the following clinical and biological factors:

• Age.
• Site of origin.
• Tumor size.
• Resectability.
• Histopathologic subtype.
• PAX3/PAX7-FOXO1 gene fusion status.
• Metastases at diagnosis.
• Lymph node involvement at diagnosis.
• Biological characteristics.
• Response to therapy.

Because treatment and prognosis partly depend on the histology and molecular genetics of the tumor, it is necessary that the tumor tissue be reviewed by pathologists and cytogeneticists/molecular geneticists with experience in the evaluation and diagnosis of tumors in children. Additionally, the diversity of primary sites, the distinctive surgical and radiation therapy treatments for each primary site, and the subsequent site-specific rehabilitation underscore the importance of treating children with rhabdomyosarcoma in medical centers with appropriate experience in all therapeutic modalities.

Age

Children aged 1 to 9 years have the best prognosis, while those younger and older fare less well. In recent Intergroup Rhabdomyosarcoma Study Group (IRSG) trials ¹⁶⁾, the 5-year failure-free survival rate was 57% for patients younger than 1 year, 81% for patients aged 1 to 9 years, and 68% for patients older than 10 years. Five-year survival rates were 76% for patients younger than one year, 87% for patients aged 1 to 9 years, and 76% for patients older than 10 years. Historical data show that adults fare less well than children (5-year overall survival [overall survival] rates, 27% ± 1.4% and 61% ± 1.4%, respectively) ¹⁷⁾.

Young age

Infants may do poorly because chemotherapy doses are reduced by 50% on the basis of reports that they have higher death rates related to chemotherapy toxicity when compared with older patients; therefore, young patients may be underdosed ¹⁸⁾. In addition, infants younger than 1 year are less likely to receive radiation therapy for local control, because of concern about the high incidence of late effects in this age group ¹⁹⁾.

The 5-year failure-free survival rate for infants was found to be 67%, compared with 81% in a matched group of older patients treated by the Children’s Oncology Group ²⁰⁾. This inferior failure-free survival rate was largely because of a relatively high rate of local failure.

In another retrospective study of 126 patients (aged ≤24 months) who were enrolled on the ARST0331 (NCT00075582) (https://clinicaltrials.gov/ct2/show/NCT00075582) and ARST0531 (NCT00354835) (https://clinicaltrials.gov/ct2/show/NCT00354835) trials, the 5-year local failure rate was 24%, the 5-year event-free survival (event-free survival) rate was 68.3%, and the overall survival rate was 81.9%. Forty-three percent of the patients had an individualized local therapy plan that more frequently omitted radiation therapy. These patients had inferior local control and event-free survival rates ²¹⁾.

Members of the Cooperative Weichteilsarkom Studiengruppe reviewed 155 patients with rhabdomyosarcoma presenting from birth to age 12 months; 144 patients had localized disease; 11 patients had metastases; 32 patients presented with alveolar rhabdomyosarcoma pathology. The following results were reported ²²⁾:

• Of the 144 patients with localized disease, 129 patients had a complete response.
• Fifty-one infants had a recurrence of their disease; 63% of patients with alveolar rhabdomyosarcoma relapsed, and 28% of patients with embryonal rhabdomyosarcoma relapsed.
• Five-year overall survival rates were 69% for patients with localized disease, 14% for patients with metastatic disease, and 41% for patients with relapsed disease.

Older children

In older children, the upper dosage limits of vincristine and dactinomycin are based on body surface area and these patients may require reduced vincristine doses because of neurotoxicity ²³⁾.

Adolescents

A report from the Associazione Italiana Ematologia Oncologia Paediatrica (AIEOP) Soft Tissue Sarcoma Committee ²⁴⁾ suggests that adolescents may have more frequent unfavorable tumor characteristics, including alveolar histology, regional lymph node involvement, and metastatic disease at diagnosis, accounting for their poor prognosis. This study also found that 5-year overall survival and progression-free survival rates were somewhat lower in adolescents than in children, but the differences among age groups younger than 1 year and aged 10 to 19 years at diagnosis were significantly worse than those in the group aged 1 to 9 years ²⁵⁾.

Adults

Adult patients with rhabdomyosarcoma have a higher incidence of pleomorphic histology (19%) than do children (<2%). Adults also have a higher incidence of tumors in unfavorable sites than do children ²⁶⁾.

Site of origin

Prognosis for childhood rhabdomyosarcoma varies according to the primary tumor site (see Table 1).

Table 1. 5-Year Survival by Primary Site of Disease

Primary Site	Number of Patients	Survival at 5 Years (%)
a) Patients treated on Intergroup Rhabdomyosarcoma Study III 27).
b) Patients treated on Intergroup Rhabdomyosarcoma Studies I–IV 28).
Orbit a	107	95
Superficial head and neck (nonparameningeal) a	106	78
Cranial parameningeal a	134	74
Genitourinary (excluding bladder/prostate) a	158	89
Bladder/prostate a	104	81
Extremity a	156	74
Trunk, abdomen, perineum, etc. a	147	67
Biliary b	25	78

Tumor size

Children with tumors 5 cm or less have improved survival compared with children with tumors larger than 5 cm ²⁹⁾. Both tumor volume and maximum tumor diameter are associated with outcome ³⁰⁾.

A retrospective review of soft tissue sarcomas in children and adolescents suggests that the 5 cm cutoff used for adults with soft tissue sarcoma may not be ideal for smaller children, especially infants. The review identified an interaction between tumor diameter and body surface area ³¹⁾. This was not confirmed by a Children’s Oncology Group study of patients with intermediate-risk rhabdomyosarcoma ³²⁾. This relationship requires prospective study to determine the therapeutic implications of the observation.

Resectability

The extent of disease after the primary surgical procedure (i.e., the Surgical-pathologic Group, also called the Clinical Group) is correlated with outcome ³³⁾. In the IRS-III study, patients with localized, gross residual disease after initial surgery (Surgical-pathologic Group III) had a 5-year survival rate of approximately 70%, compared with a rate of more than 90% for patients without residual tumor after surgery (Group I) and a rate of approximately 80% for patients with microscopic residual tumor after surgery (Group II) ³⁴⁾. Group I and Group II represent a minority of patients; approximately 50% of patients have unresectable Group III disease at time of diagnosis ³⁵⁾.

Resectability without functional impairment is related to initial size and site of the tumor and does not account for the biology of the disease. Outcome is optimized with the use of multimodality therapy. All patients require chemotherapy, and at least 85% of patients also benefit from radiation therapy, with favorable outcomes even for patients with nonresectable disease. In the IRS-IV study, the Group III patients with localized unresectable disease who were treated with chemotherapy and radiation therapy had a 5-year failure-free survival rate of about 75% and a local control rate of 87% ³⁶⁾.

Histopathologic subtype

The alveolar subtype is more prevalent among patients with less favorable clinical features (e.g., younger than 1 year or older than 10 years, extremity and truncal primary tumors, and metastatic disease at diagnosis), and is generally associated with a worse outcome than in similar patients with embryonal rhabdomyosarcoma.

• In the IRS-I and IRS-II studies, the alveolar subtype was associated with a less favorable outcome even in patients whose primary tumor was completely resected (Group I) ³⁷⁾.
• A statistically significant difference in 5-year survival by histopathologic subtype (82% for embryonal rhabdomyosarcoma vs. 65% for alveolar rhabdomyosarcoma) was not noted when 1,258
• IRS-III and IRS-IV patients with rhabdomyosarcoma were analyzed ³⁸⁾.
• In the IRS-III study, outcome for patients with Group I alveolar subtype tumors was similar to that for other patients with Group I tumors, but the alveolar patients received more intensive therapy ³⁹⁾.
• Patients with alveolar rhabdomyosarcoma who have regional lymph node involvement have significantly worse outcomes (5-year FFS, 43%) than patients who do not have regional lymph node involvement (5-year failure-free survival, 73%) ⁴⁰⁾.

Anaplasia has been observed in 13% of embryonal rhabdomyosarcoma cases and its presence may adversely influence clinical outcome in patients with intermediate-risk disease. However, anaplasia was not shown to be an independent prognostic variable in a multivariate analysis ⁴¹⁾.

PAX3/PAX7-FOXO1 gene fusion status

Occasionally, patients with histology consistent with alveolar rhabdomyosarcoma do not have one of the two gene fusions that are characteristic of the disease. Patients with translocation-negative alveolar rhabdomyosarcoma have outcomes similar to those for patients with embryonal rhabdomyosarcoma and fare better than patients with fusion-positive alveolar rhabdomyosarcoma ⁴²⁾. For example, in a study from the Soft Tissue Sarcoma Committee of the Children’s Oncology Group of 434 cases of intermediate-risk rhabdomyosarcoma, fusion-positive patients had a lower EFS rate (PAX3, 54% and PAX7, 65%) than did those with embryonal rhabdomyosarcoma (event-free survival rate, 77%).

In a Children’s Oncology Group study, patients with Stage 2 or 3, Group III PAX3-positive tumors had worse overall survival rates than did those with PAX7 tumors ⁴³⁾. Comparable results were observed in another study; patients with PAX7-positive tumors and patients with fusion-negative tumors had similar outcomes ⁴⁴⁾.

These studies also demonstrated that fusion status was a better predictor of outcome than was histology and this variable has now been incorporated into the risk stratification of patients in the current Children’s Oncology Group ARST1431 (NCT02567435) (https://www.cancer.gov/about-cancer/treatment/clinical-trials/search/v?id=NCT02567435) study for patients with intermediate-risk rhabdomyosarcoma. Similar conclusions were reached in a retrospective study of three consecutive trials in the United Kingdom. The authors underscored the probable value of treating fusion-negative patients whose tumors have alveolar histology with therapy that is stage appropriate for embryonal histology tumors ⁴⁵⁾.

Metastases at diagnosis

Children with metastatic disease at diagnosis have the worst prognosis.

The prognostic significance of metastatic disease is modified by the following:

• Tumor histology (embryonal rhabdomyosarcoma is more favorable than alveolar). Only patients with alveolar histology and regional node disease have a worse prognosis provided that the regional disease is treated with radiation therapy ⁴⁶⁾.
• Age at diagnosis (<10 years for children with embryonal rhabdomyosarcoma).
• The site of metastatic disease. Patients with metastatic genitourinary (nonbladder, nonprostate) primary tumors have a more favorable outcome than do patients with metastatic disease from other primary sites ⁴⁷⁾.
• The number of metastatic sites ⁴⁸⁾.

The Children’s Oncology Group performed a retrospective review of patients enrolled on high-risk protocols for rhabdomyosarcoma. PAX fusion status correlated with clinical characteristics at diagnosis, including age, stage, histology, and extent of metastatic disease (Oberlin status). Among patients with metastatic disease, PAX-FOXO1 fusion status was not an independent predictor of outcome ⁴⁹⁾.

Lymph node involvement at diagnosis

Lymph node involvement at diagnosis is associated with an inferior prognosis ⁵⁰⁾ and clinical and/or imaging evaluation is performed before treatment and preoperatively. Sentinel lymph node identification by appropriate methodology can aid in this evaluation. Suspicious nodes are sampled surgically with open biopsy preferred to needle aspiration, although this may occasionally be appropriate. Pathologic evaluation of clinically uninvolved nodes is site specific; in the United States, it is performed for extremity sites or for boys older than 10 years with paratesticular primaries.

Data on the frequency of lymph node involvement in various sites are useful for making clinical decisions. For example, up to 40% of patients with rhabdomyosarcoma in genitourinary sites have lymph node involvement, while patients with certain head and neck sites have a much lower likelihood (<10%). Patients with nongenitourinary pelvic sites (e.g. anus/perineum) have an intermediate frequency of lymph node involvement ⁵¹⁾.

In the extremities and select truncal sites, sentinel lymph node evaluation is a more accurate form of diagnosis than is random regional lymph node sampling. In clinically negative lymph nodes of the extremity or trunk, sentinel lymph node biopsy is the preferred form of node sampling by the Children’s Oncology Group. Technical considerations are obtained from surgical experts. Needle or open biopsy of clinically enlarged nodes is appropriate ⁵²⁾.

Radiation therapy is administered to patients with lymph node involvement in order to enhance regional control.

Biological characteristics

The embryonal and alveolar histologies have distinctive molecular characteristics that have been used for diagnostic confirmation, and may be useful for assigning risk group, determining therapy, and monitoring residual disease during treatment ⁵³⁾.

1. Embryonal histology: Embryonal tumors often show loss of heterozygosity at 11p15 and gains on chromosome 8 ⁵⁴⁾. Embryonal tumors have a higher background mutation rate and a higher single-nucleotide variant rate than do alveolar tumors, and the number of somatic mutations increases with older age at diagnosis ⁵⁵⁾. Genes with recurring mutations include those in the RAS pathway (e.g., NRAS, KRAS, HRAS, and NF1), which together are observed in approximately one-third of cases. Other genes with recurring mutations include FGFR4, PIK3CA, CTNNB1, FBXW7, and BCOR, all of which are present in fewer than 10% of cases ⁵⁶⁾. Embryonal histology with anaplasia: Anaplasia has been reported in a minority of children with rhabdomyosarcoma, primarily arising in children with the embryonal subtype who are younger than 10 years ⁵⁷⁾. Rhabdomyosarcoma with nonalveolar anaplastic morphology may be a presenting feature for children with Li-Fraumeni syndrome and germline TP53 mutations ⁵⁸⁾. Among eight consecutively presenting children with rhabdomyosarcoma and TP53 germline mutations, all showed anaplastic morphology. Among an additional seven children with anaplastic rhabdomyosarcoma and unknown TP53 germline mutation status, three of the seven children had functionally relevant TP53 germline mutations. The median age at diagnosis of the 11 children with TP53 germline mutation status was 40 months (range, 19–67 months).
2. Alveolar histology: About 70% to 80% of alveolar tumors are characterized by translocations between the FOXO1 gene on chromosome 13 and either the PAX3 gene on chromosome 2 (t(2;13)(q35;q14)) or the PAX7 gene on chromosome 1 (t(1;13)(p36;q14)) ⁵⁹⁾. Other rare fusions include PAX3-NCOA1 and PAX3-INO80D ⁶⁰⁾. Translocations involving the PAX3 gene occur in approximately 59% of alveolar rhabdomyosarcoma cases, while the PAX7 gene appears to be involved in about 19% of cases ⁶¹⁾. Patients with solid-variant alveolar histology have a lower incidence of PAX-FOXO1 gene fusions than do patients showing classical alveolar histology ⁶²⁾. For the diagnosis of alveolar rhabdomyosarcoma, a FOXO1 gene rearrangement may be detected with good sensitivity and specificity using either fluorescence in situ hybridization or reverse transcription–polymerase chain reaction ⁶³⁾. The alveolar histology that is associated with the PAX7 gene in patients with or without metastatic disease appears to occur at a younger age and may be associated with longer event-free survival rates than those associated with PAX3 gene rearrangements ⁶⁴⁾. Patients with alveolar histology and the PAX3 gene are older and have a higher incidence of invasive tumor (T2). Around 22% of cases showing alveolar histology have no detectable PAX gene translocation ⁶⁵⁾. In addition to FOXO1 rearrangements, alveolar tumors are characterized by a lower mutational burden than are fusion-negative tumors, with fewer genes having recurring mutations ⁶⁶⁾. BCOR and PIK3CA mutations and amplification of MYCN, MIR17HG, and CDK4 have also been described.
3. Spindle cell/sclerosing histology: Spindle cell/sclerosing rhabdomyosarcoma has been proposed as a separate entity in the World Health Organization Classification of Tumors of Soft Tissue and Bone ⁶⁷⁾. For congenital/infantile spindle cell rhabdomyosarcoma, a study reported that 10 of 11 patients showed recurrent fusion genes. Most of these patients had truncal primary tumors, and no paratesticular tumors were found. Novel VGLL2 rearrangements were observed in seven patients (63%), including the VGLL2-CITED2 fusion in four patients and the VGLL2-NCOA2 fusion in two patients ⁶⁸⁾. Three patients (27%) harbored different NCOA2 gene fusions, including TEAD1-NCOA2 in two patients and SRF-NCOA2 in one patient. All fusion-positive congenital/infantile spindle cell rhabdomyosarcoma patients with available long-term follow-up were alive and well, and no patients developed distant metastases ⁶⁹⁾. Further study is needed to better define the prevalence and prognostic significance of these gene rearrangements in young children with spindle cell rhabdomyosarcoma. In older children and adults with spindle cell/sclerosing rhabdomyosarcoma, a specific MYOD1 mutation (p.L122R) has been observed in a large proportion of patients ⁷⁰⁾. Activating PIK3CA mutations are seen in about one-half of the cases, and 60% of these cases have pure sclerosing morphology ⁷¹⁾. The presence of the MYOD1 mutation is associated with an increased risk of local and distant failure ⁷²⁾. In one study that included 15 children with MYOD1-mutant tumors, the most common primary site was the head and neck region ⁷³⁾. These patients had sclerosing spindle or mixed histology, and 10 of 15 patients died of disease despite aggressive multimodal therapy.

These findings highlight the important differences between embryonal and alveolar tumors. Data demonstrate that PAX-FOXO1 fusion–positive alveolar tumors are biologically and clinically different from fusion-negative alveolar tumors and embryonal tumors ⁷⁴⁾. In a study of Intergroup Rhabdomyosarcoma Study Group patients, which captured an entire cohort from a single prospective clinical trial, the outcome for patients with translocation-negative alveolar rhabdomyosarcoma was better than that observed for translocation-positive patients. The outcome was similar to that seen in patients with embryonal rhabdomyosarcoma and demonstrated that fusion status is a critical factor for risk stratification in pediatric rhabdomyosarcoma.

Genome-wide methylation assays can accurately identify PAX3 and PAX7 fusion–positive rhabdomyosarcomas, as well as wild-type and RAS mutant fusion–negative tumors ⁷⁵⁾.

Response to therapy

It is unlikely that response to induction chemotherapy, as judged by anatomic imaging, correlates with the likelihood of survival in patients with rhabdomyosarcoma, on the basis of the IRSG, Children’s Oncology Group, and International Society of Pediatric Oncology (SIOP) studies that found no association ⁷⁶⁾. However, an Italian study did find that patient response correlated with likelihood of survival ⁷⁷⁾. In patients with embryonal rhabdomyosarcoma who had metastases only in the lungs, the Cooperative Weichteilsarkom Studiengruppe assessed the relationship between complete response of the lung metastases at weeks 7 to 10 after chemotherapy and outcome in 53 patients ⁷⁸⁾. Five-year survival was 68% for 26 complete responders at weeks 7 to 10 versus 36% for 27 patients who achieved complete responses at later time points.

Other studies have investigated response to induction therapy, showing benefit to response. These data are somewhat flawed because therapy is usually tailored on the basis of response and thus, the situation is not as clear as the Children’s Oncology Group data suggests ⁷⁹⁾.

Response as judged by sequential functional imaging studies with fluorine F 18-fludeoxyglucose positron emission tomography (PET) may be an early indicator of outcome ⁸⁰⁾ and is under investigation by several pediatric cooperative groups. A retrospective analysis of 107 patients from a single institution examined PET scans performed at baseline, after induction chemotherapy, and after local therapy ⁸¹⁾. Standardized uptake value measured at baseline predicted progression-free survival and overall survival, but not local control. A negative scan after induction chemotherapy correlated with statistically significantly better progression-free survival. A positive scan after local therapy predicted worse progression-free survival, overall survival, and local control. PET scans have been shown to be useful in understanding patterns of spread, particularly in patients with extremity disease ⁸²⁾.

Rhabdomyosarcoma complications

Rhabdomyosarcoma can spread from where it started to other areas, making treatment and recovery more difficult.

As with other types of serious cancer, aggressive chemotherapy and radiation for rhabdomyosarcoma can cause substantial side effects, both in the short and long term. Your health care team takes steps to treat and manage these effects as best as possible. And it’s important for you to learn what to watch for and contact your team with any concerns.

Rhabdomyosarcoma causes

Scientists do not know what causes most cases of rhabdomyosarcoma, but they are learning how normal cells become cancerous because of certain changes in their DNA. DNA is the chemical in each of our cells that makes up our genes – the instructions for how our cells function. It is packaged in chromosomes (long strands of DNA in each cell). You normally have 23 pairs of chromosomes in each cell (one set of chromosomes comes from each parent). You usually look like your parents because they are the source of your DNA. But DNA affects more than how you look.

Some genes control when your cells grow, divide into new cells, and die. Genes that help cells grow, divide, or stay alive are called oncogenes. Others that slow down cell division or make cells die at the right time are called tumor suppressor genes. Cancers can be caused by DNA changes that turn on oncogenes or turn off tumor suppressor genes.

Certain genes in a cell can be turned on when bits of DNA are switched from one chromosome to another. This type of change, called a translocation, can happen when a cell is dividing into 2 new cells. This seems to be the cause of most cases of alveolar rhabdomyosarcoma. In these cancers, a small piece of chromosome 2 (or, less often, chromosome 1) ends up on chromosome 13. This moves a gene called PAX3 (or PAX7 if it’s chromosome 1) right next to a gene called FOXO1. The PAX genes play an important role in cell growth while an embryo’s muscle tissue is being formed, but these genes usually shut down once they’re no longer needed. The normal function of the FOXO1 gene is to activate other genes. Moving them together probably activates the PAX genes, which may be what leads to the tumor forming.

Research suggests that embryonal rhabdomyosarcoma develops in a different way. Cells of this tumor have lost a small piece of chromosome 11 that came from the mother, and it has been replaced by a second copy of that part of the chromosome from the father. This seems to make the IGF2 gene on chromosome 11 overactive. The IGF2 gene codes for a protein that can make these tumor cells grow. Other gene changes are probably important in these tumors as well.

Changes in several different genes are usually needed for normal cells to become cancer cells. Scientists have found some other gene changes that set some rhabdomyosarcoma cells apart from normal cells, but there are likely still others that haven’t been found yet.

Scientists now understand many of the gene changes that can lead to rhabdomyosarcoma, but it’s still not clear what causes these changes. Some gene changes can be inherited. Others might just be a random event that sometimes happens inside a cell, without having an outside cause. There are no known lifestyle-related or environmental causes of rhabdomyosarcoma, so it’s important to know that there is nothing children with rhabdomyosarcoma or their parents could have done to prevent these cancers.

Risk factors for rhabdomyosarcoma

A risk factor is anything that affects the chance of having a disease such as cancer. Different cancers have different risk factors.

Most cases of rhabdomyosarcoma occur sporadically, with no recognized predisposing risk factor, with the exception of the following ⁸³⁾:

• Genetic factors:
  • Li-Fraumeni cancer susceptibility syndrome (with germline TP53 mutations) ⁸⁴⁾.
  • DICER1 syndrome ⁸⁵⁾.
  • Neurofibromatosis type I ⁸⁶⁾.
  • Costello syndrome (with germline HRAS mutations) ⁸⁷⁾.
  • Beckwith-Wiedemann syndrome (more commonly associated with Wilms tumor and hepatoblastoma) ⁸⁸⁾.
  • Noonan syndrome ⁸⁹⁾.
• High birth weight and large size for gestational age are associated with an increased incidence of embryonal rhabdomyosarcoma ⁹⁰⁾.

Lifestyle-related risk factors such as body weight, physical activity, diet, and tobacco use play a major role in many adult cancers. But these factors usually take many years to influence cancer risk, and they are not thought to play much of a role in childhood cancers, including rhabdomyosarcoma.

In most cases, children with rhabdomyosarcoma have no family history of cancer. More research is needed, but the risk of the embryonal type of rhabdomyosarcoma appears to increase in people with a first-degree relative — parent, sibling or child — with cancer, especially when relatives were diagnosed with cancer before the age of 30.

In rare cases, rhabdomyosarcoma may be linked with neurofibromatosis, a genetic disorder that causes tumors to form on nerve tissue. Though more confirming research is needed, in rare cases, rhabdomyosarcoma may be linked with certain inherited syndromes such as Li-Fraumeni syndrome, Beckwith-Wiedemann syndrome or Costello syndrome.

Age and gender

Rhabdomyosarcoma is most common in children younger than 10, but it can also develop in teens and adults. It is slightly more common in boys than in girls.

Inherited conditions

Some people have a tendency to develop certain types of cancer because they have inherited changes in their DNA from their parents. Some rare inherited conditions increase the risk of rhabdomyosarcoma (and usually some other tumors as well).

• Members of families with Li-Fraumeni syndrome are more likely to develop sarcomas (including rhabdomyosarcoma), breast cancer, leukemia, and some other cancers.
• Children with Beckwith-Wiedemann syndrome have a high risk of developing Wilms tumor, a type of kidney cancer, but they are also more likely to develop rhabdomyosarcoma and some other types of childhood cancer.
• Neurofibromatosis type 1, also known as von Recklinghausen disease, usually causes multiple nerve tumors (especially in nerves of the skin), but it also increases the risk of rhabdomyosarcoma.
• Costello syndrome is very rare. Children with this syndrome have high birth weights but then fail to grow well and are short. They also tend to have a large head. They are prone to develop rhabdomyosarcoma as well as some other tumors.
• Noonan syndrome is a condition in which children tend to be short, have heart defects, and can be slower than typical children in developing physical skills and learning things. They are also at higher risk for rhabdomyosarcoma.

These conditions are rare and account for only a small fraction of rhabdomyosarcoma cases. But they suggest that the key to understanding rhabdomyosarcoma might come from studying genes and how they work in very early life to control cell growth and development.

Exposures before birth

Some studies have suggested that being exposed to x-rays before birth might be linked with an increased risk of rhabdomyosarcoma in young children. Parental use of drugs such as marijuana and cocaine has been suggested as a possible risk factor as well. But the studies that have found these links have been small, and more research is needed to see if there is a true link among these factors and rhabdomyosarcoma.

Rhabdomyosarcoma prevention

The risk of many adult cancers can be reduced with certain lifestyle changes (such as staying at a healthy weight or quitting smoking), but at this time there are no known ways to prevent most cancers in children.

The only known risk factors for rhabdomyosarcoma – age, gender, and certain inherited conditions – can’t be changed. There are no proven lifestyle-related or environmental causes of rhabdomyosarcoma, so at this time there is no way to protect against these cancers.

Even though scientists don’t know how to prevent it, most children with rhabdomyosarcoma can be treated successfully.

Rhabdomyosarcoma symptoms

Rhabdomyosarcoma can start nearly anywhere in the body, so there are no symptoms that show up in all cases. The symptoms of rhabdomyosarcoma depend on where the tumor is, how large it is, and if it has spread to other parts of the body.

• When the tumor is in the neck, chest, back, limbs, or groin (including the testicles), the first sign might be a lump or swelling. Sometimes it can cause pain, redness, or other problems.
• Tumors around the eye can cause the eye to bulge out or the child to appear to be cross-eyed. Vision might be affected as well.
• Tumors in the ear or nasal sinuses can cause an earache, headache, or sinus congestion.
• Tumors in the bladder or prostate can lead to blood in the urine, while a tumor in the vagina can cause vaginal bleeding. These tumors might grow big enough to make it hard or painful to urinate or have bowel movements.
• Tumors in the abdomen or pelvis can cause vomiting, abdominal pain, or constipation.
  rhabdomyosarcoma rarely develops in the bile ducts (small tubes leading from the liver to the intestines), but when it does it can cause yellowing of the eyes or skin (jaundice).
• If rhabdomyosarcoma becomes more advanced, it can cause symptoms such as lumps under the skin (often in the neck, under the arm, or in the groin), bone pain, constant cough, weakness, or weight loss.

One or more of these symptoms usually leads parents to bring a child to the doctor. Many of these signs and symptoms are more likely to be caused by something other than rhabdomyosarcoma. For example, children and teens can have bumps or pain from play or sports injuries. Still, if your child has any of these symptoms and they don’t go away within a week or so, check with your doctor so that the cause can be found and treated, if needed.

Can rhabdomyosarcoma be found early?

At this time, there are no widely recommended screening tests for rhabdomyosarcoma. Screening is testing for a disease such as cancer in people who don’t have any symptoms.

Still, rhabdomyosarcoma often causes symptoms that allow it to be found before it has spread to other parts of the body. For example, small tumors that start in the muscles behind the eye often make the eye bulge. Tumors in the nasal cavity often cause nasal congestion, nosebleeds, or bloody mucus. When small lumps form near the surface of the body, children or their parents often see or feel them.

Many cases of rhabdomyosarcoma start in the bladder or other parts of the urinary tract and can cause trouble emptying the bladder or blood in the urine or in diapers. Tumors starting around the testicles in young boys can cause painless swelling that is often noticed early by a parent. In girls with rhabdomyosarcoma of the vagina, the tumor might cause bleeding or a mucus-like discharge from the vagina.

It can be harder to recognize tumors in the arms, legs, and trunks of older children because they often have pain or bumps from sports or play injuries.

There are many other causes of the symptoms above, and most of them are not serious, but it is important to have them checked by a doctor. This includes having your child’s doctor check out any pain, swelling, or lumps that grow quickly or don’t go away after a week or so.

About 1 in 3 of these cancers is found early enough so that all of the visible cancer can be removed completely by surgery. But even when this happens, very small tumors (which cannot be seen, felt, or detected by imaging tests) could already have spread to other parts of the body, which is why other treatments are needed as well.

Families known to carry inherited conditions that raise the risk of rhabdomyosarcoma or that have several family members with cancer (particularly childhood cancers) should talk with their doctors about the possible need for more frequent checkups. It is not common for rhabdomyosarcoma to run in families, but close attention to possible early signs of cancer might help find it early, when treatment is most likely to be successful.

Rhabdomyosarcoma diagnosis

Certain signs and symptoms might suggest that a person has rhabdomyosarcoma, but tests are needed to find out for sure. After the patient is diagnosed with rhabdomyosarcoma, an extensive evaluation to determine the extent of the disease should be performed before instituting therapy. This evaluation typically includes the following:

1. Chest x-ray.
2. Computed tomography (CT) scan of the chest.
   • The European Pediatric Soft Tissue Sarcoma Study Group reviewed 367 patients enrolled in the CCLG-EPSSG-RMS-2005 (NCT00379457) study ⁹¹⁾. By prospective study design, patients with indeterminate pulmonary nodules identified on baseline CT scan of the chest (defined as ≤4 pulmonary nodules measuring <5 mm; or 1 nodule measuring ≥5 mm and <10 mm) received the same treatment as did patients with no pulmonary nodules identified on baseline CT of the chest. Rates of event-free survival and overall survival for both groups were the same. The authors concluded that indeterminate pulmonary nodules at diagnosis, as defined in this summary, do not affect outcome in patients with localized rhabdomyosarcoma.
3. CT scan of the abdomen and pelvis (for lower extremity or genitourinary primary tumors).
4. Magnetic resonance imaging (MRI) of the base of the skull and brain (for parameningeal primary tumors) and of the primary site of other nonparameningeal primary tumors, as appropriate.
5. Regional lymph node evaluation.
   1. CT or MRI: Cross-sectional imaging (CT or MRI scan) of regional lymph nodes should be obtained.
   2. Lymph node evaluation: Clearly enlarged lymph nodes should be biopsied when possible. Sentinel lymph node biopsy is more accurate than random lymph node sampling and is preferred in patients with extremity and trunk rhabdomyosarcoma, in which enlarged lymph nodes are not revealed on imaging or by physical examination ⁹²⁾. Many studies have demonstrated that sentinel lymph node biopsies can be safely performed in children with rhabdomyosarcoma, and tumor-positive biopsies alter the treatment plan ⁹³⁾. Pathologic evaluation of normal-appearing regional nodes is currently required for all Soft Tissue Sarcoma Committee of the Children’s Oncology Group (COG-STS) study participants with extremity and trunk primary rhabdomyosarcoma. In boys aged 10 years and older with paratesticular rhabdomyosarcoma, retroperitoneal node dissection (ipsilateral nerve sparing) is currently required for normal-appearing lymph nodes, because microscopic tumor is often documented even when the nodes are not enlarged ⁹⁴⁾. The International Society of Paediatric Oncology Malignant Mesenchymal Tumour Group has confirmed this is a necessary approach ⁹⁵⁾.
   3. Positron emission tomography (PET): PET with fluorine F 18-fludeoxyglucose scans can identify areas of possible metastatic disease not seen by other imaging modalities ⁹⁶⁾. The efficacy of these imaging studies for identifying involved lymph nodes or other sites of disease is important for staging, and PET imaging is recommended on current Soft Tissue Sarcoma Committee of the Children’s Oncology Group treatment protocols.
6. Bilateral bone marrow aspirates and biopsies for selected patients.
7. Bone scan for selected patients.

A retrospective study of 1,687 children with rhabdomyosarcoma enrolled in Intergroup Rhabdomyosarcoma Study Group (IRSG) and COG studies from 1991 to 2004 suggests those with localized negative regional lymph nodes, noninvasive embryonal tumors, and Group I alveolar tumors (about one-third of patients) can have limited staging procedures that eliminate bone marrow and bone scan examinations at diagnosis ⁹⁷⁾.

Medical history and physical exam

If your child has symptoms that could be from rhabdomyosarcoma (or another type of tumor), the doctor will want to get a complete medical history to find out more about the symptoms and how long your child has had them. The doctor will also examine your child to look for possible signs of rhabdomyosarcoma or other health problems. For example, the doctor might be able to see or feel an abnormal lump or swelling.

If the doctor suspects your child might have rhabdomyosarcoma (or another type of tumor), tests will be needed to find out. These might include imaging tests, biopsies, and/or lab tests.

Imaging tests

Imaging tests use x-rays, magnetic fields, radioactive substances, or sound waves to create pictures of the inside of the body. Imaging tests can be done for a number of reasons, including:

• To help find out if a suspicious area might be cancer
• To determine the extent of a tumor or learn how far a cancer has spread
• To help determine if treatment is working

People who have or may have rhabdomyosarcoma will get one or more of these tests.

Plain x-rays

X-rays are sometimes used to look for tumors, but their use is limited mainly to looking at bones because they don’t show much detail in internal organs. A chest x-ray is sometimes done to look for cancer that might have spread to the lungs, although it isn’t needed if a chest CT scan is being done.

Computed tomography (CT) scan

The CT scan uses x-rays to make detailed cross-sectional images of parts of the body, including soft tissues such as muscles. Instead of taking one picture, like a regular x-ray, a CT scanner takes many pictures as it rotates around your child while he or she lies on a table. A computer then combines these pictures into images of slices of the part of the body being studied.

This test can often show a tumor in detail, including how large it is and if it has grown into nearby structures. It can also be used to look at nearby lymph nodes, as well as the lungs or other areas of the body where the cancer might have spread.

Before the scan, your child may be asked to drink a contrast solution and/or get an intravenous (IV) injection of a contrast dye that will help better outline abnormal areas. Your child may need an IV line for the contrast dye. The dye can cause some flushing (a feeling of warmth, especially in the face). Some people are allergic and get hives. Rarely, more serious reactions like trouble breathing or low blood pressure can occur. Be sure to tell the doctor if your child has any allergies (especially to iodine or shellfish) or has ever had a reaction to any contrast material used for x-rays.

CT scans take longer than regular x-rays. A CT scanner has been described as a large donut, with a narrow table that slides in and out of the middle opening. Your child will need to lie still on the table while the scan is being done. Younger children may be given medicine to help keep them calm or even asleep during the test.

Magnetic resonance imaging (MRI) scan

Like CT scans, MRI scans give detailed images of soft tissues in the body. But MRI scans use radio waves and strong magnets to create the images instead of x-rays. A contrast material called gadolinium may be injected into a vein before the scan to help show details better. This contrast material usually does not cause allergic reactions.

This test might be used instead of a CT scan to look at the tumor and the tissues around it. MRI is especially useful if the tumor is in certain parts of the body, such as the head and neck, an arm or leg, or the pelvis. MRI scans can help determine the exact extent of a tumor, because they can show the muscle, fat, and connective tissue around the tumor in great detail. This is important when planning surgery or radiation therapy. MRI is also very useful if your child’s doctor is concerned about possible spread to the spinal cord or brain.

MRI scans take longer than CT scans – often up to an hour. Your child may have to lie on a table that slides inside a narrow tube, which is confining and can be distressing. The test also requires a person to stay still for several minutes at a time. Newer, more open MRI machines, which are less confining, might be an option, but the test still requires staying still for long periods of time. The MRI machine also makes loud buzzing and clicking noises that can be disturbing. Sometimes, younger children are given medicine to help keep them calm or even asleep during the test.

Bone scan

A bone scan can help show if a cancer has spread to the bones, and is often part of the workup for anyone with rhabdomyosarcoma. This test is useful because it provides a picture of the entire skeleton at once.

For this test, a small amount of low-level radioactive material is injected into a vein (IV). The amount of radioactivity used is very low and will pass out of the body within a day or so. Over a couple of hours, the substance settles in abnormal areas of bone throughout the body. Your child then lies on a table for about 30 minutes while a special camera detects the radioactivity and creates a picture of the skeleton. Younger children can be given medicine to help keep them calm or even asleep during the test.

Areas of active bone changes attract the radioactivity and show up as “hot spots” on the scan. These areas may suggest cancer in an area, but other bone diseases can also cause the same pattern, so other tests such as plain x-rays or MRI scans, or even a bone biopsy might be needed.

Positron emission tomography (PET) scan

For a PET scan, a radioactive substance (usually a type of sugar related to glucose, known as FDG) is injected into the blood. The amount of radioactivity used is very low and will pass out of the body in a day or so. Because cancer cells in the body are growing quickly, they will absorb large amounts of the sugar.

After about an hour, your child will lie on a table in the PET scanner for about 30 minutes while a special camera creates a picture of areas of radioactivity in the body. The picture is not detailed like a CT or MRI scan, but it provides helpful information about the whole body.

PET scans are not used routinely to help diagnose rhabdomyosarcoma, but they can sometimes be helpful in finding out if suspicious areas seen on other imaging tests (such as bone scans or CT scans) are tumors. PET scans can also be repeated during treatment to monitor the cancer over time.

Some machines can do a PET and CT scan at the same time (PET/CT scan). This lets the doctor compare areas of higher radioactivity on the PET scan with the more detailed appearance of that area on the CT scan.

Ultrasound

Ultrasound uses sound waves and their echoes to make a picture of internal organs or tumors. For this test, a small, microphone-like instrument called a transducer is moved around on the skin (which is first lubricated with gel). It gives off sound waves and picks up the echoes as they bounce off the organs. The echoes are converted by a computer into an image on a screen.

Ultrasound can be used to see if tumors in the pelvis (such as prostate or bladder tumors) are growing or shrinking over time. (This test can’t be used to look at tumors in the chest because the ribs block the sound waves.)

This is an easy test to have, and it uses no radiation. Your child simply lies on a table, and a doctor or technician moves the transducer over the part of the body being looked at.

Biopsy

The results of imaging tests might strongly suggest that someone has rhabdomyosarcoma, but a biopsy (removing some of the tumor for viewing under a microscope and other lab testing) is the only way to be certain. Usually several different kinds of lab tests are done on the biopsy sample to sort out what kind of tumor it is.

Biopsies can be done in several ways. The approach used depends on where the tumor is, the age of the patient, and the expertise and experience of the doctor doing the biopsy.

Surgical biopsy

The most common biopsy approach is to remove a small piece of tumor during surgery while the patient is under general anesthesia (asleep). In some cases, nearby lymph nodes are also removed to see if the tumor has spread to them. The samples are then sent to a lab and tested.

Needle biopsies

If for some reason a surgical biopsy can’t be done, a less invasive biopsy using a thin, hollow needle may be done. There are 2 kinds of needle biopsies, each of which has pros and cons.

• Core needle biopsy: For a core needle biopsy, the doctor inserts a hollow needle into the tumor to withdraw a piece of it (known as a core sample). If the tumor is just under the skin, the doctor can guide the needle into the tumor by touch. But if the tumor is deep inside the body, imaging tests such as ultrasound or CT scans might be needed to help guide the needle into place. The removed core sample is then sent to the lab for testing.

The main advantage of a core needle biopsy is that it does not require surgery, so there is no large incision. Depending on where the tumor is, adults and older children might not need general anesthesia (where they are asleep for the biopsy), but some younger children might. On the other hand, the specimen is smaller than with a surgical biopsy, and if the needle isn’t aimed correctly, it might miss the cancer. If the specimen is not a good sample of the tumor, another biopsy will be needed.

• Fine needle aspiration (FNA) biopsy: For this technique, the doctor uses a very thin, hollow needle attached to a syringe to withdraw (aspirate) a small tumor sample. An FNA biopsy is best suited for tumors that can be reached easily (such as those just under the skin), although it can also be used for tumors deeper in the body.

The downside of FNA is that the sample is very, very small. The pathologist must be experienced with this technique and be able to decide which lab tests will be most helpful on a very small sample. In cancer centers that have the experience to extract the most information from very small amounts of tissue, FNA can be a valuable – though certainly not foolproof – way to diagnose rhabdomyosarcoma, but it is not usually the preferred biopsy technique.

Bone marrow aspiration and biopsy

These tests aren’t used to diagnose rhabdomyosarcoma, but they are often done after the diagnosis to find out if the tumor has spread to the bone marrow (the soft inner parts of certain bones).

The 2 tests are usually done at the same time. The samples are usually taken from the back of both of the pelvic (hip) bones, but in some patients they may be taken from other bones.

These tests might be done during the surgery to treat the main tumor (while the child is still under anesthesia), or they might be done as a separate procedure.

If the bone marrow aspiration is being done as a separate procedure, the child lies on a table (on his or her side or belly). After cleaning the skin over the hip, the doctor numbs the area and the surface of the bone with local anesthetic, which can briefly sting or burn. In most cases, the child is also given other medicines to help them relax or even be asleep during the procedure. A thin, hollow needle is then inserted into the bone, and a syringe is used to suck out a small amount of liquid bone marrow.

A bone marrow biopsy is usually done just after the aspiration. Small pieces of bone and marrow are removed with a slightly larger needle that is pushed down into the bone. Once the biopsy is done, pressure will be applied to the site to help stop any bleeding.

The samples of bone and marrow are sent to the lab, where they are looked at and tested for cancer cells.

Lumbar puncture (spinal tap)

Lumbar puncture is not a common test for rhabdomyosarcoma, but it might be done for tumors in the head near the covering of the brain (the meninges). This test is used to look for cancer cells in the cerebrospinal fluid (CSF), which is the liquid that bathes the brain and spinal cord.

For this test, the doctor first numbs an area in the lower part of the back near the spine. The doctor may also recommend that the child be given something to make him or her sleep so the spinal tap can be done without difficulty or causing harm. A small, hollow needle is then inserted between the bones of the spine to withdraw some of the fluid, which is then sent to the lab for testing.

Lab tests on the biopsy samples

A doctor called a pathologist looks at the biopsy samples under a microscope to see if they contain cancer cells. If cancer is found, the next step is to figure out if it is rhabdomyosarcoma. In rare cases, the pathologist can see that the cancer cells have small muscle striations, which confirms that the cancer is rhabdomyosarcoma. But most often, other lab tests are needed to be sure.

The pathologist might use special stains on the samples to identify the type of tumor. The stains contain special proteins (antibodies) that attach to substances in rhabdomyosarcoma cells but not to other cancers. The stains produce a distinct color that can be seen under a microscope. This lets the pathologist know that the tumor is a rhabdomyosarcoma.

Sometimes the tumor will also be tested for gene or chromosome changes.

If a diagnosis of rhabdomyosarcoma is made, the pathologist will also use these tests to help determine which kind of rhabdomyosarcoma it is. This is important because it affects how the cancer is treated. For example, alveolar rhabdomyosarcoma, which tends to be more aggressive, typically requires more intense treatment than embryonal rhabdomyosarcoma.

Blood tests

No blood test can be used to diagnose rhabdomyosarcoma. But certain blood tests may be helpful once a diagnosis has been made.

A complete blood count (CBC) measures the levels of white blood cells, red blood cells, and platelets in the blood. If the CBC result is abnormal at the time of diagnosis it could mean the cancer has spread to the bone marrow, where these blood cells are made.

Standard blood tests are done often to check a child’s general health both before treatment (especially before surgery) and during treatment (such as chemotherapy) to look for possible problems or side effects. These tests often include a CBC to monitor bone marrow function and blood chemistry tests to measure how well the liver and kidneys are working.

Rhabdomyosarcoma Stage

Before a suspected tumor mass is biopsied, imaging studies of the mass and baseline laboratory studies should be obtained. Once rhabdomyosarcoma has been diagnosed and the type of rhabdomyosarcoma identified, doctors need to assess, as accurately as possible, how much cancer there is and where it has spread. The answers to these questions are expressed in a standard kind of shorthand known as staging.

The prognosis (outlook) for people with cancer depends, to a large extent, on the cancer’s stage. The stage of a cancer is one of the most important factors in choosing treatment.

Your child’s doctors will use the results of the imaging tests and biopsies and the direct examination of the organs during surgery to learn how far the cancer has spread. If there is any doubt about the extent of the cancer, more biopsies may be done on tissues at the edge of the tumor, nearby lymph nodes, and any suspicious lumps in other parts of the body.

To stage rhabdomyosarcoma, doctors first determine 3 key pieces of information:

1. The type of rhabdomyosarcoma (embryonal or alveolar)
2. The TNM stage
3. The clinical group

These factors are then used to divide patients into risk groups, which then are used to guide treatment.

Rhabdomyosarcoma is staged differently from most other cancers, and it can be confusing. If you have any questions about the staging or risk groups, ask the doctor or nurse to explain it to you in a way you understand.

The TNM stage

The TNM stage is determined before treatment starts, and is based on 3 key pieces of information:

• T: The characteristics of the main tumor (location and size)
• N: Whether the cancer has spread to nearby lymph nodes (bean-sized collections of immune system cells)
• M: Whether it has metastasized (spread) to distant parts of the body

These factors are combined to determine an overall stage:

Stage 1

The tumor started in a favorable area:

• The orbit (area around the eye)
• The head and neck area, except for parameningeal sites (areas next to the membranes covering the brain, such as the nasal passages and nearby sinuses, middle ear, and the uppermost part of the throat)
• A genital or urinary site, except the bladder or prostate gland
• Bile ducts (tubes leading from the liver to the intestines)

The tumor can be any size. It may have grown into nearby areas and/or spread to nearby lymph nodes, but it has not spread to distant parts of the body.

Stage 2

The tumor started in an unfavorable site:

• The bladder or prostate
• An arm or leg
• A parameningeal site (an area next to the membranes covering the brain, such as the nasal passages and nearby sinuses, middle ear, or the uppermost part of the throat)
• Any other part of the body not mentioned in stage 1

The tumor is 5 cm (about 2 inches) or smaller across and there is no evidence that it has spread to nearby lymph nodes or distant parts of the body.

Stage 3

The tumor started in an unfavorable site:

• The bladder or prostate
• An arm or leg
• A parameningeal site (an area next to the membranes covering the brain, such as the nasal passages and nearby sinuses, middle ear, or the uppermost part of the throat)
• Any other part of the body not mentioned in stage 1

And one of the following applies:

• The tumor is 5 cm across or smaller but has spread to nearby lymph nodes
• The tumor is larger than 5 cm across and may or may not have spread to nearby lymph nodes

In either case, the cancer has not spread to distant parts of the body.

Stage 4

The tumor can have started anywhere in the body and can be of any size. It has spread to distant parts of the body such as the lungs, liver, bones, or bone marrow.

Clinical group staging

The clinical group is based on the extent of the disease and how completely it is removed during initial surgery. The groups are defined as follows.

Group I

This group includes children with localized rhabdomyosarcoma (the cancer has not spread to nearby lymph nodes or to distant sites in the body) that is removed completely by surgery.

About 10% to 15% of rhabdomyosarcoma patients are in group I.

Group II

This group includes children who have had all of the visible cancer removed by surgery, but cancer cells have been found at the edges (margins) of the removed specimen (meaning that there may have been a small amount of cancer left behind), in the nearby lymph nodes, or in both places. In all cases, as much of the cancer has been removed as possible.

About 20% of rhabdomyosarcoma patients are in group II.

Group III

These children have tumors that could not be removed completely. Some tumor was left behind that could be seen with the naked eye. The cancer may have spread to nearby lymph nodes, but there is no sign that it has spread to distant organs.

About 50% of rhabdomyosarcoma patients are in group III.

Group IV

At the time of diagnosis, these children have evidence of distant cancer spread to places such as the lungs, liver, bones, bone marrow, or to distant muscles or lymph nodes.

About 15% to 20% of rhabdomyosarcoma patients are in group IV.

Risk groups

Using the information about the type of rhabdomyosarcoma, the TNM stage, and the clinical group, doctors classify patients into 3 risk groups. Information about risk groups helps doctors decide how aggressive treatment should be.

The risk groups are based on what has been learned from previous research on patients’ outcomes. The groups discussed here are based on the most current information, but these may change in the future as safer and more effective treatments are developed.

Low-risk group

About 1 in 3 children with rhabdomyosarcoma falls into the low-risk group. It includes:

• Children with TNM stage 1 embryonal rhabdomyosarcomas that fall into clinical groups I, II, or III
• Children with stage 2 or 3 embryonal rhabdomyosarcoma who are in clinical groups I or II

Intermediate-risk group

About half of children of rhabdomyosarcoma fall into the intermediate-risk group. It includes:

• Children with stage 2 or 3 embryonal rhabdomyosarcoma who are in clinical group III
• Children with alveolar rhabdomyosarcoma that has not spread to distant parts of the body (stage 1, 2, or 3)

High-risk group

This group includes:

Children with widespread (stage 4) rhabdomyosarcoma (embryonal rhabdomyosarcoma or alveolar rhabdomyosarcoma)

Rhabdomyosarcoma survival rate

Survival rates are often used by doctors as a standard way of discussing a person’s prognosis (outlook). Some people may want to know the survival statistics for those in similar situations, while others may not find the numbers helpful, or may even not want to know them.

When discussing cancer survival statistics, doctors often use a number called the 5-year survival rate. The 5-year survival rate refers to the percentage of patients who live at least 5 years after their cancer is diagnosed. Of course, many people live much longer than 5 years (and many are cured).

To get 5-year survival rates, doctors have to look at people who were treated at least 5 years ago. Improvements in treatment since then might result in a better outlook for patients being diagnosed with rhabdomyosarcoma now.

Survival rates are often based on previous outcomes of large numbers of people who had the disease, but they can’t predict what will happen in any person’s case. For a person with rhabdomyosarcoma, the risk group is important in estimating their outlook. But many other factors can also affect a person’s outlook, such as their age, the location of the tumor, certain gene changes in the cancer cells, and how well the cancer responds to treatment.

Here are general survival statistics based on risk groups. These numbers come from large clinical trials treating children with rhabdomyosarcoma in the 1980s and 1990s.

Low-risk group

Overall, the 5-year survival rate for children in the low-risk group is over 90%. Most of these children will be cured.

Intermediate-risk group

For those in the intermediate-risk group, the 5-year survival rates range from about 60% to about 80%. The rate varies based on tumor location, stage, and the age of the child (children aged 1 to 9 tend to do better than older or younger children).

High-risk group

If the cancer has spread widely, the 5-year survival rate is generally around 20% to 40%. Again, it’s important to note that other factors, such as the patient’s age and the site and type of tumor will affect these numbers. For example, children with embryonal rhabdomyosarcoma and limited spread (to only 1 or 2 distant sites) have a higher 5-year survival rate. Also, children 1 to 9 years of age tend to have a better outlook than younger or older patients.

Even when taking risk groups and other factors into account, survival rates are at best rough estimates. Your child’s doctor is your best source of information on this topic, as he or she knows your situation best.

Rhabdomyosarcoma treatment

Once rhabdomyosarcoma has been found and staged, the cancer care team will talk with you about treatment options. It’s important to be sure you understand your child’s options as well as their possible side effects to help make the decision that’s the best fit for your child. If there is anything you don’t understand, ask to have it explained.

The treatment and prognosis (outlook) for patients with rhabdomyosarcoma depend to a large extent on the type of rhabdomyosarcoma and on how much of it can be removed with surgery. This is why it’s very important for patients to be diagnosed and treated by doctors who have experience with rhabdomyosarcoma. Children with rhabdomyosarcoma are best treated in a cancer center where there is experience and expertise in treating childhood cancers, such as in centers who are members of the Children’s Oncology Group.

For children and teens, a team approach is recommended that includes specialists at a children’s cancer, as well as the child’s pediatrician. For adults with rhabdomyosarcoma, the treatment team typically includes specialists at a major cancer center, as well as the patient’s primary care doctor. Doctors on the treatment team might include:

• An orthopedic surgeon (a surgeon who specializes in muscles and bones) who is experienced in treating rhabdomyosarcoma
• A medical or pediatric oncologist (a doctor who treats cancer with chemotherapy and other drugs)
• A radiation oncologist (a doctor who treats cancer with radiation therapy)
• A pathologist (a doctor specializing in using lab tests to diagnose and classify diseases)
• A physiatrist (a doctor who directs a person’s rehabilitation and physical therapy after treatment)

The team might also include other doctors, as well as physician assistants, nurse practitioners, nurses, psychologists, social workers, physical therapists and other rehabilitation specialists, and other health professionals. Going through cancer treatment often means meeting lots of specialists and learning about parts of the medical system you probably haven’t been exposed to before.

The types of treatment that can be used for rhabdomyosarcoma include:

• Surgery
• Chemotherapy
• Radiation therapy
• High-dose chemotherapy and stem cell transplant (very rarely)
• Clinical trials. Clinical trials are studies to investigate new ways of treating cancer. Many of the advances in treating pediatric cancers, including rhabdomyosarcoma, come from clinical trials of the Children’s Oncology Group, which has more than 200 participating medical institutions from the United States and other countries.

All children and adults with rhabdomyosarcoma will be treated with surgery to remove the tumor if it can be done without causing major damage or disfigurement. If this isn’t possible, chemotherapy and/or radiation therapy may be used first to try to shrink the tumor. If it shrinks enough, surgery can be done at this point. The goal of surgery is to remove the tumor completely, but this isn’t always possible.

Whether the tumor appears to have been removed completely or not, all patients with rhabdomyosarcoma need chemotherapy. Without it, it’s very likely that the cancer will come back in distant parts in the body because small amounts of cancer have almost always reached other parts of the body when the cancer is first found.

If cancer is left behind after surgery or if the cancer has some less favorable traits and it hasn’t spread to distant sites (as is the case most of the time), radiation therapy will also be given.

Many of these treatments can be used again if the cancer continues to grow or if it comes back later on.

All of these treatments can have side effects, but many of them can be made less troublesome. Your medical team will help you take care of the side effects and help you understand and deal with the medical problems, stress, and other issues related to treatment.

Because many of these things can be more complex for cancer in children, many people will be involved in your child’s overall care. As a parent, taking care of a child with cancer can be a very big job. It’s important to remember that you will have a lot of help. It’s also important for you to know that the health care professionals who treat children with rhabdomyosarcoma are using the experience and knowledge gained from many decades of detailed scientific study of treating this disease.

Embryonal rhabdomyosarcoma treatment

This type tends to occur in children under 15 and in the head and neck region and the bladder or genital area.

With embryonal rhabdomyosarcoma, the position in the body can decide the treatment.

Surgery may be the initial treatment. Chemotherapy tends to work well for this type of sarcoma. You may have chemotherapy before surgery to shrink a tumor and make it easier to remove. Or it may be given after surgery to try to reduce the chance of the tumor coming back.

If the tumor is in a place where it is not possible to remove it completely with surgery (for example, behind the nose or in the eye socket), your doctor will treat it with a combination of radiotherapy and chemotherapy.

Alveolar rhabdomyosarcoma treatment

This occurs in the arms or legs of older children and young people but can also occur in the muscles of the trunk.

With alveolar rhabdomyosarcoma, usually the tumor is removed with surgery and then you have radiotherapy to the area where the tumor was.

The radiotherapy aims to reduce the chance of the tumor coming back in the same place. Chemotherapy is usually be given before or after the surgery.

Anaplastic rhabdomyosarcoma and undifferentiated sarcoma treatment

This type of rhabdomyosarcoma usually occurs in adults and in the arms or legs.

With anaplastic rhabdomyosarcoma and undifferentiated sarcoma, usually the treatment is surgery and then radiotherapy.

The radiotherapy aims to reduce the chance of the tumor coming back in the same place. Chemotherapy tends not to work very well and so is not usually used.

Coping and support

A diagnosis of rhabdomyosarcoma can be frightening — especially for the family of a newly diagnosed child. Coping with a diagnosis of a rare cancer can be especially difficult, both practically and emotionally. Being well informed about your cancer and its treatment can make it easier to make decisions and cope with what happens. With time you’ll find ways to cope with the distress and uncertainty of cancer. Until then, you may find it helps to:

• Learn enough about rhabdomyosarcoma to make decisions about care. Ask your doctor about this sarcoma, including treatment options. As you learn more, you may become more confident in understanding and making decisions about treatment options. If your child has cancer, ask the health care team for guidance on sharing this information in a caring and age-appropriate way.
• Keep friends and family close. Keeping your close relationships strong can help you deal with cancer. Friends and relatives can provide the practical support you’ll need, such as helping take care of your house if your child is in hospital. And they can serve as emotional support when you feel overwhelmed.
• Ask about mental health support. The concern and understanding of a counselor, medical social worker, psychologist or other mental health professional also may help you. If your child has cancer, ask your health care team for advice on providing emotional and social support and options for professional mental health support. You can also check online for a cancer organization, such as the National Cancer Institute ⁹⁸⁾ or the American Cancer Society ⁹⁹⁾, that lists support services.

Osteosarcoma

Osteosarcoma also called osteogenic sarcoma, is the most common type of cancer that starts in the bones. The cancer cells in these tumors look like early forms of bone cells that normally help make new bone tissue, but the bone tissue in an osteosarcoma is not as strong as that of normal bones. Most osteosarcomas occur in children and young adults. Teenagers are the most commonly affected age group, but osteosarcoma can develop at any age.

Osteosarcoma is most often found in the long bones, more often the legs, but sometimes the arms, but it can start in any bone. In very rare instances, it occurs in soft tissue outside the bone.

In children and young adults, osteosarcoma usually starts in areas where the bone is growing quickly, such as near the ends of the leg or arm bones:

• Most tumors develop in the bones around the knee, either in the distal femur (the lower part of the thigh bone) or the proximal tibia (the upper part of the shinbone).
• The upper arm bone close to the shoulder (proximal humerus) is the next most common site.

Still, osteosarcoma can develop in any bone, including the bones of the pelvis (hips), shoulder, and jaw. This is especially true in older adults.

Treatment usually involves chemotherapy, surgery and, sometimes, radiation therapy. Doctors select treatment options based on where the osteosarcoma starts, the size of the cancer, the type and grade of the osteosarcoma, and whether the cancer has spread beyond the bone.

Treatment innovations for osteosarcoma have greatly improved the outlook (prognosis) for this cancer over the years. After completion of treatment, lifelong monitoring is recommended to watch for potential late effects of intense treatments.

Osteosarcoma subtypes

Based on how the cells look under the microscope, osteosarcomas can be classified as high grade, intermediate grade, or low grade. The grade of the tumor tells doctors how likely it is that the cancer will grow and spread to other parts of the body.

High-grade osteosarcomas

These are the fastest growing types of osteosarcoma. When seen with a microscope, they do not look like normal bone and have many cells in the process of dividing into new cells. Most osteosarcomas that occur in children and teens are high grade. There are many types of high-grade osteosarcomas (although the first 3 are the most common).

• Osteoblastic
• Chondroblastic
• Fibroblastic
• Small cell
• Telangiectatic
• High-grade surface (juxtacortical high grade)

Other high-grade osteosarcomas include:

• Pagetoid: a tumor that develops in someone with Paget disease of the bone
• Extraskeletal: a tumor that starts in a part of the body other than a bone (but still makes bone tissue)
• Post-radiation: a tumor that starts in a bone that had once been treated with radiation

Intermediate-grade osteosarcomas

These uncommon tumors fall between high-grade and low-grade osteosarcomas. They are usually treated the same way as low-grade osteosarcomas.

• Periosteal (juxtacortical intermediate grade)

Low-grade osteosarcomas

These are the slowest-growing osteosarcomas. The tumors look more like normal bone and have few dividing cells when seen with a microscope.

• Parosteal (juxtacortical low grade)
• Intramedullary or intraosseous well differentiated (low-grade central)

The grade of the tumor plays a role in determining its stage and the type of treatment used.

Osteosarcoma causes

It’s not clear what causes osteosarcoma. Doctors know bone cancers form when something goes wrong in one of the cells that are responsible for making new bone.

Osteosarcoma begins when a healthy bone cell develops changes in its DNA. A cell’s DNA contains the instructions that tell a cell what to do. The changes tell the cell to start making new bone when it isn’t needed. The result is a mass (tumor) of poorly formed bone cells that can invade and destroy healthy body tissue. Cells can break away and spread (metastasize) throughout the body.

The DNA mutations that cause some inherited forms of bone cancers are known. In many cases, genetic testing can be used to see if someone has one of these mutations.

However, most bone cancers are not caused by inherited DNA mutations. They’re the result of mutations during the person’s lifetime. These mutations may result from exposure to radiation or cancer-causing chemicals, but most often they occur for no apparent reason. These mutations are present only in the cancer cells, so they cannot be passed on to the person’s children.

Risk factors for developing osteosarcoma

These factors increase the risk of osteosarcoma:

• Previous treatment with radiation therapy
• Other bone disorders, such as Paget’s disease of bone and fibrous dysplasia
• Certain inherited or genetic conditions, including hereditary retinoblastoma, Bloom syndrome, Li-Fraumeni syndrome, Rothmund-Thomson syndrome and Werner syndrome

Genetic disorders

A very small number of bone cancers especially osteosarcomas appear to be hereditary and are caused by defects (mutations) in certain genes. Retinoblastoma is a rare eye cancer in children that can be hereditary. The inherited form of retinoblastoma is caused by a mutation (abnormal copy) of the RB1 gene. Those with this mutation also have an increased risk of developing bone or soft tissue sarcomas. Also, if radiation therapy is used to treat the retinoblastoma, the risk of osteosarcoma in the bones around the eye is even higher.

Finally, there are families with several members who have developed osteosarcoma without inherited changes in any of the known genes. The gene defects that may cause cancers in these families haven’t been discovered yet.

Paget disease

Paget disease is a benign (non-cancerous) but pre-cancerous condition that affects one or more bones. It results in formation of abnormal bone tissue and occurs mostly in people older than 50. Affected bones are heavy, thick, and brittle. They are weaker than normal bones and more likely to fracture (break). Most of the time, Paget disease is not life threatening. Bone cancer (usually osteosarcoma) develops in about 1% of those with Paget disease, usually when many bones are affected.

Radiation

Bones that have been exposed to ionizing radiation may also have a higher risk of developing bone cancer. A typical x-ray of a bone is not dangerous, but exposure to large doses of radiation does pose a risk. For example, radiation therapy to treat cancer can cause a new cancer to develop in one of the bones in the treatment area. Being treated when you are younger and/or being treated with higher doses of radiation (usually over 60 Gy) increases your risk of developing bone cancer.

Exposure to radioactive materials such as radium and strontium can also cause bone cancer because these minerals build up in bones.

Non-ionizing radiation, like microwaves, electromagnetic fields from power lines, cellular phones, and household appliances, does not increase bone cancer risk.
Bone marrow transplantation

Osteosarcoma has been reported in a few patients who have undergone bone marrow (stem cell) transplantation.

Injuries

People have wondered if injury to a bone can cause cancer. This has never been proven. Many people with bone cancer remember having hurt that part of their bone. Most doctors believe that these injuries did not cause the cancer. Instead, the cancer caused people to remember the incident or that the injury drew their attention to that bone, making them notice a problem that had already been present for some time.

Osteosarcoma symptoms

Signs and symptoms of osteosarcoma may include, among others:

• Swelling near a bone
• Bone or joint pain
• Bone injury or bone break for no clear reason

Pain

Pain in the affected bone is the most common sign of bone cancer. At first, the pain is not constant. It may be worse at night or when the bone is used, for instance, leg pain when walking. As the cancer grows, the pain will be there all the time, and get worse with activity.

Swelling

Swelling in the area of the pain may not occur until weeks later. It might be possible to feel a lump or mass depending on where the tumor is.

Cancers in the bones of the neck can cause a lump in the back of the throat that can lead to trouble swallowing or make it hard to breathe.

Fractures

Bone cancer can weaken the bone it’s in, but most of the time the bones do not fracture (break). People with a fracture next to or through a bone tumor usually describe sudden severe pain in a bone that had been sore for a few months.

Other symptoms

Cancer in the bones of the spine can press on nerves, causing numbness and tingling or even weakness.

Cancer can cause weight loss and fatigue. If the cancer spreads to internal organs it may cause other symptoms, too. For instance, if the cancer spreads to the lungs, it can cause trouble breathing.

These symptoms are more often due to conditions other than cancer, such as injuries or arthritis. Still, if these problems go on for a long time without a known reason, you should see your doctor.

Osteosarcoma complications

Complications of osteosarcoma and its treatment include:

• Cancer that spreads (metastasizes). Osteosarcoma can spread from where it started to other areas, making treatment and recovery more difficult. Osteosarcoma that spreads most often spreads to the lungs and to other bones.
• Adapting to limb amputation. Surgery that removes the tumor and spares the limb is used whenever possible. But sometimes it’s necessary to remove part of the affected limb in order to remove all of the cancer. Learning to use an artificial limb (prosthesis) will take time, practice and patience. Experts can help you adapt.
• Long-term treatment side effects. The aggressive chemotherapy needed to control osteosarcoma can cause substantial side effects, both in the short and long term. Your health care team can help you manage the side effects that happen during treatment and provide you with a list of side effects to watch for in the years after treatment.

Tumor-specific complications

Complications of the tumor itself include pathological fractures. These may occur at presentation or during preoperative chemotherapy. As mentioned above, patients in both these scenarios have poorer outcomes than those without pathological fractures ¹⁾.

Biopsy-related complications

When devising an approach to biopsy a lesion concerning for osteosarcoma (or any sarcoma, for that matter), careful planning of the biopsy approach is necessary to lower the potential for tumor cells to seed the biopsy tract and surrounding tissues. A biopsy tract that extends across multiple compartments may necessitate a larger field of resection, which increases the risk of treatment-related complications ²⁾.

Treatment-related complications

• Chemotherapy side effects
  • When utilizing chemotherapy, the majority of the major side effects occur during the treatment process. Nausea, malaise, alopecia, anemia, and anorexia are possible but usually resolve shortly after completion of the chemotherapy cycle. There are, however, some long-term side effects, which may include cardiotoxicity, pulmonary toxicity, and gradual hearing loss. There are reports of later development of a secondary malignancy ³⁾.
• Radiation side effects
  • Radiation is known to impart superficial side effects, including skin dryness, itching, peeling, and uncommonly, burns. Menstrual changes, erectile dysfunction, and infertility are all reported adverse events in cases of pelvic radiation. When the chest and abdomen are involved in radiation treatment, diarrhea, incontinence, rectal bleeding, nausea, vomiting, dry mouth, dysphagia, pneumonitis, and fibrosis are possible. Much like chemotherapy, there is a small risk of late development of a secondary malignancy ⁴⁾.
• Periprosthetic infection
  • Prostheses-related infections are a relatively frequent complication (approximately 10% of limb salvage surgeries) most often due to lengthy surgery time, repeated surgery at the same site, and immunosuppression secondary to chemotherapy. First-line treatment of these periprosthetic infections typically involves one or more debridement procedures with both local and systemic antibiotic therapy (systemic and local antibiotic cement beads). If these efforts are ineffective, the implant requires removal, followed by debridement and wash out. A cement spacer impregnated with an antibiotic generally gets placed before the insertion of a new prosthesis. Ultimately, amputation may be necessary for a number of these patients ⁵⁾.
• Implant failure
  • The most common reason for reconstruction failure is the mechanical breakdown of the mega prosthesis. Mechanical failure necessitates the replacement of the prosthetic. The tibia is the most frequent site of mechanical failure ⁶⁾.
• Fracture/non-union of allograft/autograft
  • Fracture/non-union of allograft/autograft reconstruction is a relatively infrequent complication, but it does occur. Chemotherapy, radiation, and extracorporeal treatment of autograft bone have been reported to increase the risk of these complications. Refractory cases may necessitate metallic implant placement or amputation ⁷⁾.

Osteosarcoma diagnosis

To diagnose osteosarcoma, the doctor may begin with a physical exam to better understand the symptoms.

Imaging tests

Imaging tests help your doctor investigate your bone symptoms, look for cancer and look for signs that the cancer has spread.

Imaging tests may include:

• X-ray
• Computerized tomography (CT)
• Magnetic resonance imaging (MRI)
• Positron emission tomography (PET)
• Bone scan

X-rays

Most bone cancers show up on x-rays of the bone. The bone at the site of the cancer may look “ragged” instead of solid. The cancer can also appear as a hole in the bone. Sometimes doctors can see a tumor around the defect in the bone that might extend into nearby tissues (such as muscle or fat). The radiologist (doctor who specializes in reading x-rays) can often tell if a tumor is malignant by the way it appears on the x-ray, but only a biopsy can tell for sure.

A chest x-ray is often done to see if bone cancer has spread to the lungs.

Computed tomography (CT) scans

CT scans are helpful in staging cancer. They help show if the bone cancer has spread to your lungs, liver, or other organs. The scans show the lymph nodes and distant organs where there might be cancer spread.

CT scans can also be used to guide a biopsy needle into a tumor. This is called a CT-guided needle biopsy. For this test, you stay on the CT scanning table while a radiologist moves a biopsy needle toward the tumor. CT scans are repeated until the tip of the needle is within the mass. (See Needle biopsy below.)

Magnetic resonance imaging (MRI) scans

MRI scans are often the best test for outlining a bone tumor. They are very helpful for looking at the brain and spinal cord.

Radionuclide bone scans

Bone scans can show if a cancer has spread to other bones. It can find smaller areas of metastasis than regular x-rays. Bone scans also can show how much damage the cancer has caused in the bone.

Areas of diseased bone will be seen on the bone scan as dense, gray to black areas, called “hot spots.” These areas suggest cancer is present, but arthritis, infection, or other bone diseases can also cause hot spots. Other imaging tests or a bone biopsy may be needed to know what’s causing the change.

Positron emission tomography (PET or PET) scans

PET scans use glucose (a form of sugar) that’s attached to a radioactive atom. A special camera can detect the radioactivity. Cancer cells absorb a lot of the radioactive sugar because of their high rate of metabolism. PET scans are useful in looking for cancer throughout your entire body. It can sometimes help tell if a tumor is cancer or not cancer (benign). It’s often combined with CT scans to better pinpoint some kinds of cancer.

Biopsy or removing a sample of cells for testing

A biopsy procedure is used to collect a sample of suspicious cells for laboratory testing. Tests can show whether the cells are cancerous. Lab tests can determine the type of cancer and whether it’s aggressive (the grade).

Types of biopsy procedures used to diagnose osteosarcoma include:

• Needle biopsy. The doctor inserts a thin needle through the skin and guides it into the tumor. The needle is used to remove small pieces of tissue from the tumor.
  • There are 2 types of needle biopsies: fine (aspiration) and core. For both types, a drug is first used to numb the area for the biopsy.
    1. For fine needle aspiration (FNA), the doctor uses a very thin needle and a syringe to take out a small amount of fluid and some cells from the tumor. Sometimes, the doctor can aim the needle by feeling the tumor if it’s near the surface of the body. If the tumor is too deep to feel, the doctor can guide the needle while looking a CT scan. This is called a CT guided needle biopsy and it is often done by an x-ray specialist known as an interventional radiologist.
    2. In a core needle biopsy, the doctor uses a larger needle to remove a small cylinder of tissue (about 1/16 inch in diameter and 1/2 inch long). Many experts feel that a core needle biopsy is better than FNA to diagnose a primary bone cancer.
• Surgical biopsy. In this procedure, a surgeon needs to cut through the skin to reach the tumor to remove a small piece of tissue. This is also called an incisional biopsy. If the entire tumor is removed (not just a small piece), it’s called an excisional biopsy. These biopsies are often done with the patient under general anesthesia (drugs are used to put you into a deep asleep). They can also be done using a nerve block, which numbs a large area. If this type of biopsy is needed, it’s important that the surgeon who will later remove the cancer also be the one to do the biopsy.

Determining the type of biopsy needed and the specifics of how it should be performed requires careful planning by the medical team. Doctors need to perform the biopsy in a way that won’t interfere with future surgery to remove the cancer. For this reason, ask your doctor for a referral to a team of experts with extensive experience in treating osteosarcoma before the biopsy.

Osteosarcoma staging

After someone is diagnosed with osteosarcoma, doctors will try to figure out if it has spread, and if so, how far. This process is called staging. The stage of a cancer describes how much cancer is in the body. It helps determine how serious the cancer is and how best to treat it. Doctors also use a cancer’s stage when talking about survival statistics.

The stage of an osteosarcoma is based on the results of physical exams, imaging tests, and any biopsies that have been done.

A staging system is a standard way for the cancer care team to sum up the extent of the cancer. When trying to figure out the best course of treatment, doctors often use a simple system that divides osteosarcomas into 2 groups: localized and metastatic. Doctors can also use more formal staging systems to describe the extent of an osteosarcoma in more detail.

Two popular systems exist for the staging of bone tumors. The Musculoskeletal Tumor Society’s Enneking system is used primarily by orthopedic surgeons because it takes into account the anatomic location of the tumor: intracompartmental (completely contained within the bone) versus extracompartmental (extension outside of the bone). The alternative system described by the American Joint Committee on Cancer does not take anatomic location into account. However, it does account for the size of the tumor, which research has recognized as having significant prognostic value for predicting response to treatment and overall survival. Specifically, larger lesions have a propensity to metastasize, so these patients may benefit from chemotherapeutic intervention, making the American Joint Committee on Cancer (AJCC) system more popular with oncologists ⁸⁾.

Osteosarcoma staging can be confusing. If you have any questions about the stage of the cancer, ask someone on your cancer care team to explain it to you in a way you understand.

Localized osteosarcoma

A localized osteosarcoma is seen only in the bone it started in and possibly the tissues next to the bone, such as muscle, tendon, or fat.

About 4 out of 5 osteosarcomas appear to be localized when they are first found. But even when imaging tests don’t show that the cancer has spread to distant areas, most patients are likely to have very small areas of cancer spread that can’t be detected with tests. This is why chemotherapy is an important part of treatment for most osteosarcomas. If it isn’t given, the cancer is more likely to come back after surgery.

Doctors further divide localized osteosarcomas into 2 groups:

• Resectable cancers are those in which all of the visible tumor can be removed by surgery.
• Non-resectable (or unresectable) osteosarcomas can’t be removed completely by surgery.

Metastatic osteosarcoma

A metastatic osteosarcoma has clearly spread to other parts of the body. Most often it spreads to the lungs, but it can also spread to other bones, the brain, or other organs.

About 1 out of 5 osteosarcomas has spread at the time of diagnosis. These cancers are harder to treat, but some can be cured if the metastases can be removed by surgery. The cure rate for these cancers improves markedly if chemotherapy is also given.

Musculoskeletal Tumor Society Staging System

A system commonly used to stage osteosarcoma is the Musculoskeletal Tumor Society staging system, also known as the Enneking system. It is based on 3 key pieces of information:

1. The grade (G) of the tumor, which is a measure of how likely it is to grow and spread, based on how it looks under the microscope. Tumors are either low grade (G1) or high grade (G2). Low-grade tumor cells look more like normal cells and are less likely to grow and spread quickly, while high-grade tumor cells look more abnormal.
2. The extent of the primary tumor (T), which is classified as either intracompartmental (T1), meaning it has basically remained within the bone, or extracompartmental (T2), meaning it has extended beyond the bone into other nearby structures.
3. If the tumor has metastasized (M), which means it has spread to nearby lymph nodes (bean-sized collections of immune system cells) or other organs. Tumors that have not spread to the lymph nodes or other organs are considered M0, while those that have spread are M1.

These factors are combined to give an overall stage, using Roman numerals from I to III. Stages I and II are further divided into A for intracompartmental tumors or B for extracompartmental tumors.

Musculoskeletal Tumor Society Enneking system for staging of malignant musculoskeletal tumors ⁹⁾

• Stage IA: Low grade, Intracompartmental tumor location, no metastasis
• Stage IB: Low grade, Extracompartmental tumor location, no metastasis
• Stage IIA: High grade, Intracompartmental tumor location, no metastasis
• Stage IIB: High grade, Extracompartmental tumor location, no metastasis
• Stage III: Any grade, Any location, Metastasis present

Table 1. Musculoskeletal Tumor Society Enneking system for staging of malignant musculoskeletal tumors

Stage	Grade	Tumor	Metastasis
IA	G1	T1	M0
IB	G1	T2	M0
IIA	G2	T1	M0
IIB	G2	T2	M0
III	G1 or G2	T1 orT2	M1

[Source ¹⁰⁾ ]

In summary:

• Low-grade, localized tumors are stage I.
• High-grade, localized tumors are stage II.
• Metastatic tumors (regardless of grade) are stage III.

The TNM staging system

Another system sometimes used to stage bone cancers (including osteosarcomas) is the American Joint Commission on Cancer (AJCC) TNM system ¹¹⁾. This system is based on 4 key pieces of information:

• T describes the size of the main (primary) tumor and if it appears in different areas of the bone.
• N describes the extent of spread to nearby (regional) lymph nodes. Bone tumors rarely spread to the lymph nodes.
• M indicates if the cancer has metastasized (spread) to other organs of the body. (The most common sites of spread are to the lungs or other bones.)
• G stands for the grade of the tumor, which describes how the cells look under a microscope. Low-grade tumor cells look more like normal cells and are less likely to grow and spread quickly, while high-grade tumor cells look more abnormal.

Numbers after T, N, M, and G provide more details about each of these factors.

The scale used for grading bone cancer is from 1 to 3. Low-grade cancers (G1) tend to grow and spread more slowly than high-grade (G2 or G3) cancers.

• Grade 1 (G1) means the cancer looks much like normal bone tissue.
• Grade 3 (G3) means the cancer looks very abnormal.
• Grade 2 (G2) falls somewhere in between.

Once the T, N, and M categories and the grade of the bone cancer have been determined, the information is combined into an overall stage. These stages (which are different from those of the Musculoskeletal Tumor Society staging system) are described by Roman numerals from I to IV (1 to 4), and are sometimes divided further.

The staging system described below is the most recent American Joint Committee on Cancer (AJCC) system effective January 2018 and applies to bone cancers of the appendicular skeleton (such as bones in the arms and legs), trunk, skull, and facial bones. Bone cancers of the pelvis and spine use different T categories and it is best to speak with your doctor about your stage for these specific cancers.

Numbers or letters after T, N, and M provide more details about each of these factors. Higher numbers mean the cancer is more advanced. Once a person’s T, N, and M categories have been determined, this information is combined in a process called stage grouping to assign an overall stage.

Cancer staging can be complex, so ask your doctor to explain it to you in a way you understand.

American Joint Committee on Cancer (AJCC) system for staging of primary bone sarcomas (8th edition) ¹²⁾:

• Stage IA: Low grade, less than 8 cm tumor size, No spread to regional lymph nodes, No distant metastasis
• Stage IB: Low grade, greater than 8 cm tumor size or skip lesions, No spread to regional lymph nodes, No distant metastasis
• Stage IIA: High grade, greater than 8 cm tumor size, No spread to regional lymph nodes, No distant metastasis
• Stage IIB: High grade, less than 8 cm tumor size, No spread to regional lymph nodes, No distant metastasis
• Stage III: High grade, Discontinuous tumor involvement/”skip” lesions, No regional lymph nodes, No distant metastasis
• Stage IVA: Any grade, Any size, No regional lymph node spread, Lung metastasis
• Stage IVB: Any grade, Any size, Regional lymph node spread, Lung or extrapulmonary metastasis

The staging system in the table below uses the pathologic stage (also called the surgical stage). It is determined by examining tissue removed during an operation. Sometimes, if surgery is not possible right away or at all, the cancer will be given a clinical stage instead. This is based on the results of a physical exam, biopsy, and imaging tests. The clinical stage will be used to help plan treatment. Sometimes, though, the cancer has spread further than the clinical stage estimates, and may not predict the patient’s outlook as accurately as a pathologic stage.

Table 2. American Joint Committee on Cancer bone cancer staging system

AJCC stage	Stage grouping	Stage description*
IA	T1 N0 M0 G1 or GX	The cancer is 8 centimeters (cm) across (about 3 inches) or smaller(T1). It has not spread to nearby lymph nodes (N0) or to distant sites (M0). The cancer is low grade (G1) or the grade cannot be determined (GX).
IB	T2 N0 M0 G1 or GX	The cancer is larger than 8 cm (3 inches) across (T2). It has not spread to nearby lymph nodes (N0) or to distant sites (M0). The cancer is low grade (G1) or the grade cannot be determined (GX).
	OR
	T3 N0 M0 G1 or GX	The cancer is in more than one place on the same bone (T3). It has not spread to nearby lymph nodes (N0) or to distant sites (M0). The cancer is low grade (G1) or the grade cannot be determined (GX).
IIA	T1 N0 M0 G2 or G3	The cancer is 8 centimeters (cm) across (about 3 inches) or less (T1). It has not spread to nearby lymph nodes (N0) or to distant sites (M0). The cancer is high grade (G2 or G3).
IIB	T2 N0 M0 G2 or G3	The cancer is larger than 8 cm (3 inches) across (T2). It has not spread to nearby lymph nodes (N0) or to distant sites (M0). The cancer is high grade (G2 or G3).
III	T3 N0 M0 G2 or G3	The cancer is in more than one place on the same bone (T3). It has not spread to nearby lymph nodes (N0) or to distant sites (M0). The cancer is high grade (G2 or G3).
IVA	Any T N0 M1a Any G	The cancer can be any size and may be in more than one place in the bone (Any T) AND has not spread to nearby lymph nodes (N0). It has spread only to the lungs (M1a). The cancer can be any grade (Any G).
IVB	Any T N1 Any M Any G	The cancer can be any size and may be in more than one place in the bone (Any T) AND it has spread to nearby lymph nodes (N1). It may or may not have has spread to distant organs like the lungs or other bones (Any M). The cancer can be any grade (Any G).
	OR
	Any T Any N M1b Any G	The cancer can be any size and may be in more than one place in the bone (Any T) and it might or might not have spread to nearby lymph nodes (Any N). It has spread to distant sites like other bones, the liver or brain (M1b). The cancer can be any grade (Any G).

Footnote: * The following additional categories are not listed on the table above:

• TX: Main tumor cannot be assessed due to lack of information.
• T0: No evidence of a primary tumor.
• NX: Regional lymph nodes cannot be assessed due to lack of information.

Osteosarcoma treatment

Osteosarcoma treatment typically involves surgery and chemotherapy. Radiation therapy might be an option in certain situations.

Successful treatment generally requires the combination of effective systemic chemotherapy and complete resection of all clinically detectable disease. Protective weight bearing is recommended for patients with tumors of weight-bearing bones to prevent pathological fractures that could preclude limb-preserving surgery.

It is imperative that patients with proven or suspected osteosarcoma have an initial evaluation by an orthopedic oncologist familiar with the surgical management of this disease. This evaluation, which includes imaging studies, should be done before the initial biopsy, because an inappropriately performed biopsy may jeopardize a limb-sparing procedure.

Randomized clinical trials have established that both neoadjuvant and adjuvant chemotherapy are effective in preventing relapse in patients with clinically nonmetastatic tumors ¹³⁾. The Pediatric Oncology Group conducted a study in which patients were randomly assigned to either immediate amputation or amputation after neoadjuvant therapy. A large percentage of patients declined to be assigned randomly, and the study was terminated without approaching the stated accrual goals. In the small number of patients treated, there was no difference in outcome for those who received preoperative versus postoperative chemotherapy ¹⁴⁾.

The treatment of osteosarcoma also depends on the histologic grade, as follows:

• High-grade osteosarcoma. High-grade osteosarcoma requires surgery and systemic chemotherapy whether it arises in the conventional central location or on a bone surface.
• Low-grade osteosarcoma. Low-grade osteosarcoma can be treated successfully by wide surgical resection alone, regardless of site of origin.
• Intermediate-grade osteosarcoma. Pathologists sometimes characterize tumors as intermediate-grade osteosarcoma. It is difficult to make treatment decisions for intermediate-grade tumors. When a tumor biopsy suggests an intermediate-grade osteosarcoma, an option is to proceed with wide resection. The availability of the entire tumor allows the pathologist to examine more tissue and evaluate soft tissue and lymphovascular invasion, which can often clarify the nature of the lesion.

If the lesion proves to have high-grade elements, systemic chemotherapy is indicated, just as it would be for any high-grade osteosarcoma. The Pediatric Oncology Group performed a study in which high-grade osteosarcoma patients were randomly assigned to either immediate definitive surgery followed by adjuvant chemotherapy or to an initial period of chemotherapy followed by definitive surgery ¹⁵⁾. The outcome was the same for both groups. Although the strategy of initial chemotherapy followed by definitive surgery has become an almost universally applied approach for osteosarcoma, this study suggests that there is no increased risk of treatment failure if definitive surgery is done before chemotherapy begins; this can help to clarify equivocal diagnoses of intermediate-grade osteosarcoma.

Recognition of intraosseous well-differentiated osteosarcoma and parosteal osteosarcoma is important because these tumor types are associated with the most favorable prognosis and can be treated successfully with wide excision of the primary tumor alone ¹⁶⁾. Periosteal osteosarcoma has a generally good prognosis ¹⁷⁾ and treatment is guided by histologic grade ¹⁸⁾.

Table 3 describes the treatment options for localized, metastatic, and recurrent osteosarcoma and malignant fibrous histiocytoma of bone.

Table 3. Treatment Options for Osteosarcoma and Malignant Fibrous Histiocytoma (MFH) of Bone

Treatment Group		Treatment Options
Localized osteosarcoma and malignant fibrous histiocytoma of bone		Surgical removal of primary tumor.
		Chemotherapy.
		Radiation therapy, if surgery is not feasible or surgical margins are inadequate.
Osteosarcoma and malignant fibrous histiocytoma of bone with metastatic disease at diagnosis:		Chemotherapy.
	Lung-only metastases	Preoperative chemotherapy followed by surgery to remove the tumor.
	Bone-only metastases or bone with lung metastases	Preoperative chemotherapy followed by surgery to remove the primary tumor and all metastatic disease (usually lungs) followed by postoperative combination chemotherapy.
		Surgery to remove the primary tumor followed by chemotherapy and then surgical resection of metastatic disease (usually lungs).
Recurrent osteosarcoma and malignant fibrous histiocytoma of bone:		Surgery to remove all sites of metastatic disease.
		Chemotherapy.
		Targeted therapy.
	Lung-only recurrence	Surgery to remove the tumor.
	Recurrence with bone-only metastases	Surgery to remove the tumor.
		153Sm-EDTMP with or without stem cell support.
	Second recurrence of osteosarcoma	Surgery to remove the tumor.

Abbreviation: 153Sm-EDTMP = samarium Sm 153-ethylenediamine tetramethylene phosphonic acid.

[Source ¹⁹⁾ ]

Surgery

The goal of surgery is to remove all of the cancer cells. But planning the operation also takes into consideration how it will affect your ability to go about your daily life. The extent of surgery for osteosarcoma depends on several factors, such as the size of the tumor and its location.

Operations used to treat osteosarcoma include:

• Surgery to remove the cancer only (limb-sparing surgery). Most osteosarcoma operations can be done in a way that removes all of the cancer and spares the limb so that function can be maintained. Whether this procedure is an option depends, in part, on the extent of the cancer and how much muscle and tissue need to be removed. If a section of bone is removed, the surgeon will reconstruct the bone. The method of reconstruction depends on your particular situation, but options include metal prosthetics or bone grafts.
• Surgery to remove the affected limb (amputation). With advancements in limb-sparing surgery, the need for amputation — removing a limb or part of a limb — has greatly reduced over the years. If amputation is necessary, advances in prosthetic joints can significantly improve outcomes and function.
• Surgery to remove the lower portion of the leg (rotationplasty). In this surgery, sometimes used for children who are still growing, the surgeon removes the cancer and surrounding area, including the knee joint. The foot and ankle are then rotated, and the ankle functions as a knee. A prosthesis is used for the lower leg and foot. Results typically enable the person to function very well in physical activities, sports and daily living.

In general, more than 80% of patients with extremity osteosarcoma can be treated by a limb-sparing procedure and do not require amputation ²⁰⁾. Limb-sparing procedures are planned only when the preoperative staging indicates that it would be possible to achieve wide surgical margins. In one study, patients undergoing limb-salvage procedures who had poor histologic response and close surgical margins had a high rate of local recurrence ²¹⁾.

Reconstruction after limb-sparing surgery can be accomplished with many options, including metallic endoprosthesis, allograft, vascularized autologous bone graft, and rotationplasty. An additional option, osteogenesis distraction bone transport, is available for patients whose tumors do not involve the epiphysis of long bones ²²⁾. This procedure results in a stable reconstruction that functionally restores the normal limb.

The choice of optimal surgical reconstruction involves many factors, including the following ²³⁾:

• Site and size of the primary tumor.
• Ability to preserve the neurovascular supply of the distal extremity.
• Age of the patient and potential for additional growth.
• Needs and desires of the patient and family for specific functions such as sports participation.

If a complicated reconstruction delays or prohibits the resumption of systemic chemotherapy, limb preservation may endanger the chance for cure. Retrospective analyses have shown that delay (≥21 days) in resumption of chemotherapy after definitive surgery is associated with increased risk of tumor recurrence and death.

For some patients, amputation remains the optimal choice for management of the primary tumor. A pathologic fracture noted at diagnosis or during preoperative chemotherapy does not preclude limb-salvage surgery if wide surgical margins can be achieved ²⁴⁾. If the pathologic examination of the surgical specimen shows inadequate margins, an immediate amputation should be considered, especially if the histologic necrosis after preoperative chemotherapy was poor ²⁵⁾.

The German Cooperative Osteosarcoma Study performed a retrospective analysis of 1,802 patients with localized and metastatic osteosarcoma who underwent surgical resection of all clinically detectable disease ²⁶⁾. Local recurrence (n = 76) was associated with a high risk of death from osteosarcoma. Factors associated with an increased risk of local recurrence included nonparticipation in a clinical trial, pelvic primary site, limb-preserving surgery, soft tissue infiltration beyond the periosteum, poor pathologic response to initial chemotherapy, failure to complete planned chemotherapy, and performing the biopsy at an institution different from where the definitive surgery is being performed.

Patients who undergo amputation have lower local recurrence rates than do patients who undergo limb-salvage procedures ²⁷⁾. There is no difference in overall survival between patients initially treated with amputation and those treated with a limb-sparing procedure. Patients with tumors of the femur have a higher local recurrence rate than do patients with primary tumors of the tibia or fibula. Rotationplasty and other limb-salvage procedures have been evaluated for both their functional outcome and their effect on survival. While limb-sparing resection is the current practice for local control at most pediatric institutions, there are few data to indicate that salvage of the lower limb is substantially superior to amputation with regard to patient quality of life ²⁸⁾.

Chemotherapy

Chemotherapy uses drugs to kill cancer cells. Chemotherapy treatment usually combines two or more drugs that can be administered as an infusion into a vein (IV), in pill form, or through both methods. For osteosarcoma, chemotherapy is often recommended before surgery (neoadjuvant therapy). Doctors monitor how the cancer cells respond to the chemotherapy in order to plan further treatments.

If the osteosarcoma shrinks in response to the chemotherapy, it may make limb-sparing surgery possible.

If the osteosarcoma doesn’t respond to treatment, it may indicate the cancer is very aggressive. Doctors may recommend a different combination of chemotherapy drugs or suggest a more aggressive operation to ensure all the cancer is removed.

Chemotherapy can also be used after surgery to kill any cancer cells that might remain.

If osteosarcoma returns after surgery or spreads to other areas of the body, chemotherapy might be recommended to try to slow the growth of the disease.

Preoperative chemotherapy

Almost all patients receive intravenous preoperative chemotherapy as initial treatment. However, a standard chemotherapy regimen has not been determined. Current chemotherapy protocols include combinations of the following agents: high-dose methotrexate, doxorubicin, cyclophosphamide, cisplatin, ifosfamide, etoposide, and carboplatin ²⁹⁾.

Preoperative chemotherapy evidence:

1. A meta-analysis of protocols for the treatment of osteosarcoma concluded that regimens containing three active chemotherapy agents were superior to regimens containing two active agents ³⁰⁾.
   • The meta-analysis also concluded that regimens with four active agents were not superior to regimens with three active agents.
   • The meta-analysis suggested that three-drug regimens that did not include high-dose methotrexate were inferior to three-drug regimens that did include high-dose methotrexate.
2. An Italian study used regimens containing fewer courses of high-dose methotrexate and observed a lower probability for event-free survival (event-free survival) than did earlier studies that used regimens containing more courses of high-dose methotrexate ³¹⁾.
3. The Children’s Oncology Group (COG) performed a prospective randomized trial in newly diagnosed children and young adults with localized osteosarcoma. All patients received cisplatin, doxorubicin, and high-dose methotrexate. One-half of the patients were randomly assigned to receive ifosfamide. In a second randomization, one-half of the patients were assigned to receive the biological compound muramyl tripeptide-phosphatidyl ethanolamine encapsulated in liposomes (L-MTP-PE) beginning after definitive surgical resection ³²⁾.
   • The addition of ifosfamide did not improve outcome.
   • The addition of L-MTP-PE produced improvement in event-free survival, which did not meet the conventional test for statistical significance, and a significant improvement in overall survival (78% vs. 70%).
   • There has been speculation regarding the potential contribution of postrelapse treatment, although there were no differences in the postrelapse surgical approaches in the relapsed patients. The appropriate role of L-MTP-PE in the treatment of osteosarcoma remains under discussion ³³⁾.
4. The Children’s Oncology Group performed a series of pilot studies in patients with newly diagnosed localized osteosarcoma ³⁴⁾.
   1. In pilot one, patients with lower degrees of necrosis after three-drug initial therapy received subsequent therapy with a higher cumulative dose of doxorubicin of 600 mg/m2.
   2. In pilot two, all patients received four-drug initial chemotherapy with cisplatin, doxorubicin, high-dose methotrexate, and ifosfamide. Patients with lower degrees of necrosis received subsequent chemotherapy with a higher cumulative dose of doxorubicin of 600 mg/m2.
   3. In pilot three, all patients received the same four-drug initial chemotherapy as pilot two. Patients with lower degrees of necrosis received higher doses of ifosfamide with the addition of etoposide in subsequent therapy.

1. • Outcomes for all three pilot studies were similar to each other and to historical controls.
   • All patients received dexrazoxane before each dose of doxorubicin. The addition of dexrazoxane did not appear to decrease the rate of good necrosis after initial therapy or event-free survival.
   • Left ventricular fractional shortening, as measured by echocardiography, was minimally affected at 78 weeks from study entry.
   • There was no evidence for an increased risk of secondary leukemia.

Postoperative chemotherapy

Historically, the extent of tumor necrosis was used in some clinical trials to determine postoperative chemotherapy. In general, if tumor necrosis exceeded 90%, the preoperative chemotherapy regimen was continued. If tumor necrosis was less than 90%, some groups incorporated drugs not previously utilized in the preoperative therapy.

Patients with less necrosis after initial chemotherapy have a prognosis that is inferior to the prognosis for patients with more necrosis. The prognosis is still substantially better than the prognosis for patients treated with surgery alone and no adjuvant chemotherapy. Based on the following evidence, it is inappropriate to conclude that patients with less necrosis have not responded to chemotherapy and that adjuvant chemotherapy should be withheld for these patients. Chemotherapy after definitive surgery should include the agents used in the initial phase of treatment unless there is clear and unequivocal progressive disease during the initial phase of therapy.

Postoperative chemotherapy evidence:

1. In an early experience, the German cooperative osteosarcoma group performed a trial in which the chemotherapy regimen for patients with poor necrosis was changed after initial treatment ³⁵⁾. The agents used before surgery were discontinued and other agents were substituted. The results were substantially poorer for these patients than for patients who continued to receive the same agents.
2. A limited-institution pilot trial tested the strategy of discontinuing the agents used in the initial phase of therapy for patients with poorer necrosis; postoperative therapy consisted of melphalan with autologous stem cell reconstitution ³⁶⁾. Five-year event-free survival for this group was 28%, which was lower than was observed in many large series in which agents were continued despite a lesser degree of necrosis.
3. Addition of cisplatin. The approach to incorporate drugs not previously used for preoperative therapy was based on early reports from Memorial Sloan Kettering Cancer Center (MSKCC) that suggested that adding cisplatin to postoperative chemotherapy improved the outcome for patients with less than 90% tumor necrosis ³⁷⁾. With longer follow-up, the outcome for patients with less than 90% tumor necrosis treated at Memorial Sloan Kettering Cancer Center was the same whether they did or did not receive cisplatin in the postoperative phase of treatment ³⁸⁾. Subsequent trials performed by other groups failed to demonstrate improved event-free survival when drugs not included in the preoperative regimen were added to postoperative therapy ³⁹⁾.
4. Addition of interferon or high-dose therapy.
   • The international European and American Osteosarcoma Study Group consortium (EURAMOS) was formed to conduct a large prospective, randomized trial to help determine whether modifying the chemotherapy regimen on the basis of the degree of necrosis would improve event-free survival. All patients received initial therapy with cisplatin, doxorubicin, and high-dose methotrexate. Patients with more than 90% necrosis were randomly assigned to continue the same chemotherapy after surgery or to receive the same chemotherapy with the addition of interferon. The addition of interferon did not improve the probability of event-free survival ⁴⁰⁾.
   • In the same EURAMOS trial, patients with less than 90% necrosis were randomly assigned to continue the same chemotherapy or to receive the same chemotherapy with the addition of high-dose ifosfamide and etoposide (MAPIE). With a median follow-up of over 61 months, the event-free survival did not differ between the two groups. The intensification of treatment in the MAPIE group resulted in greater toxicity than did the treatment in the standard methotrexate arm ⁴¹⁾.

Other chemotherapy approaches not considered effective

The Italian Sarcoma Group and the Scandinavian Sarcoma Group performed a clinical trial in patients with osteosarcoma who presented with clinically detectable metastatic disease ⁴²⁾. Consolidation with high-dose etoposide and carboplatin followed by autologous stem cell reconstitution did not appear to improve outcome and the investigators do not recommend this strategy for the treatment of osteosarcoma.

Laboratory studies using cell lines and xenografts suggested that bisphosphonates had activity against osteosarcoma ⁴³⁾. A single-institution clinical trial demonstrated that pamidronate could safely be administered contemporaneously with multiagent chemotherapy to patients with newly diagnosed osteosarcoma ⁴⁴⁾. The French pediatric and adult sarcoma cooperative groups performed a prospective trial for the treatment of osteosarcoma ⁴⁵⁾. All patients received multiagent chemotherapy, and patients were randomly assigned to receive or not to receive zoledronate. The addition of zoledronate did not improve event-free survival.

Radiation therapy

Radiation therapy uses high-energy beams, such as X-rays and protons, to kill cancer cells. Radiation might be an option in certain situations, such as when surgery isn’t possible or if surgeons can’t remove all of the cancer during an operation ⁴⁶⁾.

During radiation therapy, the beams of energy are delivered from a machine that moves around you as you lie on a table. The beams are carefully directed to the area of the osteosarcoma in order to reduce the risk of damage to surrounding healthy cells.

Radiation therapy should be considered in patients with osteosarcoma of the head and neck who have positive or uncertain resection margins ⁴⁷⁾. While it is accepted that the standard approach is primary surgical resection, a retrospective analysis of a small group of highly selective patients reported long-term event-free survival with external-beam radiation therapy for local control in some patients ⁴⁸⁾.

Investigators from a single institution reported on 28 children and young adults with osteosarcoma who were treated with radiation therapy for local control ⁴⁹⁾. Sixteen patients received radiation therapy during the primary treatment course, and 12 patients received radiation therapy as part of retrieval therapy after recurrence. For patients who received radiation therapy during primary treatment, the cumulative incidence of local failure at 5 years was 25%; for patients with recurrent disease, the cumulative incidence of local failure at 5 years was 44%. Local tumor progression was observed in 3 of 13 patients (23%) who were treated with adjuvant radiation therapy after resection, while three of six patients (50%) who received definitive radiation therapy as a sole modality of local control experienced local progression.

Treatment of osteosarcoma metastasis

Approximately 20% to 25% of patients with osteosarcoma present with clinically detectable metastatic disease. For patients with metastatic disease at initial presentation, roughly 20% will remain continuously free of disease, and roughly 30% will survive 5 years from diagnosis ⁵⁰⁾.

The lung is the most common site of initial metastatic disease ⁵¹⁾. Patients with metastases limited to the lungs have a better outcome than do patients with metastases to other sites or to the lungs combined with other sites ⁵²⁾.

Treatment options for patients with osteosarcoma or malignant fibrous histiocytoma of bone with metastatic disease at diagnosis include the following:

1. Chemotherapy. The chemotherapeutic agents used include high-dose methotrexate, doxorubicin, cisplatin, high-dose ifosfamide, etoposide, and, in some reports, carboplatin or cyclophosphamide.
   • Chemotherapy evidence:
     • High-dose ifosfamide (17.5 g per course) in combination with etoposide produced a complete response (10%) or partial response (49%) in patients with newly diagnosed metastatic osteosarcoma ⁵³⁾.
     • However, similar to localized disease, there is no evidence that the addition of ifosfamide or etoposide contributes to improved event-free survival or overall survival in patients with metastatic disease, and the addition of these agents is up to physician discretion in this setting.
     • The addition of either muramyl tripeptide or ifosfamide to a standard chemotherapy regimen that included cisplatin, high-dose methotrexate, and doxorubicin was evaluated using a factorial design in patients with metastatic osteosarcoma (n = 91) ⁵⁴⁾. There was a nominal advantage for the addition of muramyl tripeptide (but not for ifosfamide) in terms of event-free survival and overall survival, but criteria for statistical significance were not met.

Treatment options for patients with metastatic lung lesions

Treatment options for patients with metastatic lung lesions include the following:

Preoperative chemotherapy followed by surgery to remove the tumor. Patients with metastatic lung lesions as the sole site of metastatic disease should have the lung lesions resected if possible. Generally, this is performed after administration of preoperative chemotherapy. In approximately 10% of patients, all lung lesions disappear after preoperative chemotherapy ⁵⁵⁾. Complete resection of pulmonary metastatic disease can be achieved in a high percentage of patients with residual lung nodules after preoperative chemotherapy. The cure rate is essentially zero without complete resection of residual pulmonary metastatic lesions.

For patients who present with primary osteosarcoma and metastases limited to the lungs and who achieve complete surgical remission, 5-year event-free survival is approximately 20% to 25%. Multiple metastatic nodules confer a worse prognosis than do one or two nodules, and bilateral lung involvement is worse than unilateral ⁵⁶⁾. Patients with peripheral lung lesions may have a better prognosis than patients with central lesions ⁵⁷⁾. Patients with fewer than three nodules confined to one lung may achieve a 5-year event-free survival of approximately 40% to 50% ⁵⁸⁾.

Treatment options for bone-only metastases or bone with lung metastases

The second most common site of metastasis is another bone that is distant from the primary tumor. Patients with metastasis to other bones distant from the primary tumor experience roughly 10% event-free survival and overall survival ⁵⁹⁾. In the Italian experience, of the patients who presented with primary extremity tumors and synchronous metastasis to other bones, only 3 of 46 patients remained continuously disease-free 5 years later ⁶⁰⁾. Patients who have transarticular skip lesions have a poor prognosis ⁶¹⁾.

Multifocal osteosarcoma is different from osteosarcoma that presents with a clearly delineated primary lesion and limited bone metastasis. Multifocal osteosarcoma classically presents with symmetrical, metaphyseal lesions, and it may be difficult to determine the primary lesion. Patients with multifocal bone disease at presentation have an extremely poor prognosis. No patient with synchronous multifocal osteosarcoma has ever been reported to be cured, but systemic chemotherapy and aggressive surgical resection may achieve significant prolongation of life ⁶²⁾.

Treatment options for patients with bone-only or bone with lung metastases include the following:

1. Preoperative chemotherapy followed by surgery to remove the primary tumor and all metastatic disease (usually lungs) followed by postoperative combination chemotherapy.
2. Surgery to remove the primary tumor followed by chemotherapy and then surgical resection of metastatic disease (usually lungs).

When the usual treatment course of preoperative chemotherapy followed by surgical ablation of the primary tumor and resection of all overt metastatic disease (usually lungs) followed by postoperative combination chemotherapy cannot be used, an alternative treatment approach may be used. This alternative treatment approach begins with surgery for the primary tumor, followed by chemotherapy, and then surgical resection of metastatic disease (usually lungs). This alternative approach may be appropriate in patients with intractable pain, pathologic fracture, or uncontrolled infection of the tumor when initiation of chemotherapy could create risk of sepsis.

Clinical trials

Clinical trials are studies to investigate new ways of treating cancer. Ask your doctor or your child’s doctor about whether you may be eligible to join a trial.

Osteosarcoma prognosis

In general, prognostic factors for osteosarcoma have not been helpful in identifying patients who might benefit from treatment intensification or who might require less therapy while maintaining an excellent outcome.

Patients with localized osteosarcoma undergoing surgery and chemotherapy have a 5-year overall survival of 62% to 65% ⁶³⁾. Based on data from the Surveillance, Epidemiology, and End Results (SEER) 2010–2016, the 5-Year Relative Survival of patients diagnosed with bone cancer is 66 percent ⁶⁴⁾. Because survival statistics are based on large groups of people, they cannot be used to predict exactly what will happen to an individual patient. No two patients are entirely alike, and treatment and responses to treatment can vary greatly. Complete surgical resection is crucial for patients with localized osteosarcoma; however, at least 80% of patients treated with surgery alone will develop metastatic disease ⁶⁵⁾. Randomized clinical trials have established that adjuvant chemotherapy is effective in preventing relapse or recurrence in patients with localized resectable primary tumors ⁶⁶⁾.

Pretreatment factors

Pretreatment factors that influence outcome include the following ⁶⁷⁾:

• Primary tumor site and initial treatment.
• Size of the primary tumor.
• Presence of clinically detectable metastatic disease.

After administration of preoperative chemotherapy, factors that influence outcome include the following:

• Surgical resectability of primary tumor.
• Degree of tumor necrosis.

Primary tumor site and initial treatment

The site of the primary tumor is a significant prognostic factor for patients with localized disease. Among extremity tumors, distal sites have a more favorable prognosis than do proximal sites. Patients with tumors located in the axial skeleton tend to fare worse compared to those diagnosed in the appendicular skeleton. A difference of up to 10 years of survival exists between groups. Axial skeleton primary tumors are associated with the greatest risk of progression and death, primarily related to the inability to achieve a complete surgical resection. Furthermore, patients with femoral tumors often do much worse than patients with lesions located in the distal tibia ⁶⁸⁾.

Prognostic considerations for the axial skeleton and extraskeletal sites are as follows:

• Pelvis: Pelvic osteosarcomas make up 7% to 9% of all osteosarcomas; survival rates for patients with pelvic primary tumors are 20% to 47% ⁶⁹⁾. Complete surgical resection is associated with positive outcome for osteosarcoma of the pelvis in some cohorts of patients ⁷⁰⁾.
• Craniofacial/head and neck: In patients with craniofacial osteosarcoma, those with primary sites in the mandible and maxilla have a better prognosis than do patients with other primary sites in the head and neck ⁷¹⁾. For patients with osteosarcoma of craniofacial bones, complete resection of the primary tumor with negative margins is essential for cure ⁷²⁾. When treated with surgery alone, patients who have osteosarcoma of the head and neck have a better prognosis than those who have appendicular lesions. Despite a relatively high rate of inferior necrosis after neoadjuvant chemotherapy, fewer patients with craniofacial primaries develop systemic metastases than do patients with osteosarcoma originating in the extremities ⁷³⁾. A meta-analysis concluded that systemic adjuvant chemotherapy improves the prognosis for patients with osteosarcoma of the head and neck, while small series have not shown a benefit for using adjuvant chemotherapy in these patients ⁷⁴⁾. Another large meta-analysis detected no benefit of chemotherapy for patients with osteosarcoma of the head and neck, but suggested that the incorporation of chemotherapy into treatment of patients with high-grade tumors may improve survival ⁷⁵⁾. A retrospective analysis identified a trend toward better survival in patients with high-grade osteosarcoma of the mandible and maxilla who received adjuvant chemotherapy ⁷⁶⁾. Radiation therapy was found to improve local control, disease-specific survival, and overall survival in a retrospective study of osteosarcoma of the craniofacial bones that had positive or uncertain margins after surgical resection ⁷⁷⁾. Radiation-associated craniofacial osteosarcomas are generally high-grade lesions, usually fibroblastic, and tend to recur locally with a high rate of metastasis ⁷⁸⁾.
• Extraskeletal: Osteosarcoma in extraskeletal sites is rare in children and young adults. With current combined-modality therapy, the outcome of patients with extraskeletal osteosarcoma appears to be similar to that of patients with primary tumors of bone ⁷⁹⁾.

Size of the primary tumor

In some series, patients with larger or bulky tumors appeared to have a worse prognosis than did patients with smaller tumors ⁸⁰⁾. One study found that the morbidity likelihood is 3.4 times higher in larger masses (over 15 cm). When tumor volume exceeds 200 mL, patients are significantly less likely to have successful limb salvage; they also demonstrate a poorer response to chemotherapy and a greater likelihood of recurrence. Tumor size has been assessed by longest single dimension, cross-sectional area, or estimate of tumor volume; all assessments have correlated with outcome. Unsurprisingly, the chance of death is significantly higher in patients with evidence of metastasis on presentation ⁸¹⁾.

Serum lactate dehydrogenase (LDH), which also correlates with outcome, is a likely surrogate for tumor volume.

Presence of clinically detectable metastatic disease

Patients with localized disease have a much better prognosis than do patients with overt metastatic disease. As many as 20% of patients will have radiographically detectable metastases at diagnosis, with the lung being the most common site ⁸²⁾. The prognosis for patients with metastatic disease appears to be determined largely by site(s) of metastases, number of metastases, and surgical resectability of the metastatic disease ⁸³⁾.

• Site of metastases: Prognosis appears more favorable for patients with fewer pulmonary nodules and for those with unilateral rather than bilateral pulmonary metastases ⁸⁴⁾; not all patients with suspected pulmonary metastases at diagnosis have osteosarcoma confirmed at the time of lung resection. In one large series, approximately 25% of patients had exclusively benign lesions removed at the time of surgery ⁸⁵⁾.
• Number of metastases: Patients with skip metastases (at least two discontinuous lesions in the same bone) have been reported to have inferior prognoses ⁸⁶⁾. However, an analysis of the German Cooperative Osteosarcoma Study experience suggests that skip lesions in the same bone do not confer an inferior prognosis if they are included in planned surgical resection. Skip metastasis in a bone other than the primary bone should be considered systemic metastasis ⁸⁷⁾. Historically, metastasis across a joint was referred to as a skip lesion. Skip lesions across a joint might be considered hematogenous spread and have a worse prognosis ⁸⁸⁾. Patients with multifocal osteosarcoma (defined as multiple bone lesions without a clear primary tumor) have an extremely poor prognosis ⁸⁹⁾.
• Surgical resectability of metastases: Patients who have complete surgical ablation of the primary and metastatic tumor (when confined to the lung) after chemotherapy may attain long-term survival, although overall event-free survival remains about 20% to 30% for patients with metastatic disease at diagnosis ⁹⁰⁾.

Surgical resectability of primary tumor

Resectability of the tumor is a critical prognostic feature because osteosarcoma is relatively resistant to radiation therapy. Complete resection of the primary tumor and any skip lesions with adequate margins is generally considered essential for cure. A retrospective review of patients with craniofacial osteosarcoma performed by the cooperative German-Austrian-Swiss osteosarcoma study group reported that incomplete surgical resection was associated with inferior survival probability ⁹¹⁾. In a European cooperative study, the size of the margin was not significant. However, prognosis was better when both the biopsy and resection were performed at a center with orthopedic oncology experience ⁹²⁾.

For patients with axial skeletal primaries who either do not undergo surgery for their primary tumor or who undergo surgery that results in positive margins, radiation therapy may improve survival ⁹³⁾.

Degree of tumor necrosis

Most treatment protocols for osteosarcoma use an initial period of systemic chemotherapy before definitive resection of the primary tumor (or resection of sites of metastases). The pathologist assesses necrosis in the resected tumor. Patients with at least 90% necrosis in the primary tumor after induction chemotherapy have a better prognosis than do patients with less necrosis ⁹⁴⁾. Patients with less necrosis (<90%) in the primary tumor after initial chemotherapy have a higher rate of recurrence within the first 2 years than do patients with a more favorable amount of necrosis (≥90%) ⁹⁵⁾.

Less necrosis should not be interpreted to mean that chemotherapy has been ineffective; cure rates for patients with little or no necrosis after induction chemotherapy are much higher than cure rates for patients who receive no chemotherapy. A review of two consecutive prospective trials performed by the Children’s Oncology Group showed that histologic necrosis in the primary tumor after initial chemotherapy was affected by the duration and intensity of the initial period of chemotherapy. More necrosis was associated with better outcome in both trials, but the magnitude of the difference between patients with more and less necrosis was diminished with a longer and more intensive period of initial chemotherapy ⁹⁶⁾.

Additional prognostic factors

Other prognostic factors include the following:

• Subsequent neoplasms. Patients with osteosarcoma as a subsequent neoplasm, including tumors arising in a radiation field, share the same prognosis as patients with de novo osteosarcoma if they are treated aggressively with complete surgical resection and multiagent chemotherapy ⁹⁷⁾. In a German series, approximately 25% of patients with craniofacial osteosarcoma had osteosarcoma as a second tumor, and in 8 of these 13 patients, osteosarcoma arose after treatment for retinoblastoma. In this series, there was no difference in outcome for primary or secondary craniofacial osteosarcoma ⁹⁸⁾.
• Age. Patients in the older adolescent and young adult age group, typically defined as age 18 to 40 years, tend to have a worse prognosis ⁹⁹⁾. Middle-age patients (over 40 years old) have considerably worse survival rates than younger adults even after the exclusion of secondary forms of osteosarcoma. Several studies have determined that patients over the age of 40 were more apt to have involvement of the axial skeleton and metastatic lesions on presentation, which correlate with poorer outcomes (as described below). Older patients (older than 60 years) fare the worst, typically due to refusal of chemotherapy and radical surgery ¹⁰⁰⁾.
• Gender. Men reportedly demonstrate less response to chemotherapy, a higher propensity for recurrence, and a four-fold increase in morbidity. Conversely, female sex correlated with a higher percentage of chemo-related tumor necrosis as well as greater overall survival ¹⁰¹⁾.
• Laboratory abnormalities. Possible prognostic factors identified for patients with conventional localized high-grade osteosarcoma include the LDH level, alkaline phosphatase (ALP) level, and histologic subtype ¹⁰²⁾. Serum alkaline phosphatase, a biomarker associated with bone turnover, has been found in elevated levels in patients with osteosarcoma. However, it is crucial to consider the age of the patient when interpreting ALP levels as intrinsically higher values are typical in younger age groups. Research has documented high levels in association with less disease-free survival. However, serum alkaline phosphatase levels may be normal at the time of diagnosis in nearly half of patients, particularly in cases where a tumor features minimal osteoid deposition ¹⁰³⁾. Lactate dehydrogenase (LDH) is also a useful biomarker. Significantly higher serum LDH levels have been observed in patients with metastasis on initial presentation than patients with local disease alone ¹⁰⁴⁾.
• Body mass index. Higher body mass index at initial presentation is associated with worse overall survival ¹⁰⁵⁾.
• Pathologic fracture. Some studies have suggested that pathologic fracture at diagnosis or during preoperative chemotherapy does not have adverse prognostic significance ¹⁰⁶⁾. Osteosarcoma patients have an increased risk of local recurrence and a decreased rate of survival if a pathological fracture is a feature of the initial presentation. Pathological fractures sustained during preoperative chemotherapy have been found to have a decreased rate of survival compared with patients without therapy-associated pathologic fracture ¹⁰⁷⁾. However, a systematic review of nine cohort studies examined the impact of pathologic fracture on outcome in osteosarcoma. The review included 2,187 patients, and 311 of these patients had pathologic fracture. The presence of pathologic fracture correlated with decreased event-free survival and overall survival ¹⁰⁸⁾. In two additional series, pathologic fracture at diagnosis was associated with a worse overall outcome ¹⁰⁹⁾. A retrospective analysis of 2,847 patients with osteosarcoma from the German cooperative group identified 321 patients (11.3%) with pathological fracture prior to the initiation of systemic therapy ¹¹⁰⁾. In pediatric patients, overall survival and event-free survival did not differ significantly between patients with and without pathologic fracture. In adults, the 5-year overall survival rate in patients with pathologic fracture was 46% versus 69% for patients without pathologic fracture. The 5-year event-free survival rate in adults was 36% for patients with pathologic fracture versus 56% for patients without pathologic fracture. In a multivariable analysis, the presence of a pathologic fracture was not a statistically significant factor for overall survival or event-free survival in the total cohort or in pediatric patients. In adult patients, pathologic fracture remained an independent prognostic factor for overall survival (hazard ratio, 1.893).
• Histology. The role of histology in response to chemotherapy and survival outcome is modest. Fibroblastic differentiation is generally considered to be favorable histology. This histologic profile is associated with improved chemotherapy-related tumor necrosis as well as a lower risk of death than alternative histologic subtypes. Chondroid predominant tumor histology correlates with poorer outcomes ¹¹¹⁾.
• Preoperative chemotherapeutic response. Survival outcome is dependent upon several factors, but the most important predictor of success is the degree of chemotherapy-induced tumor necrosis; Necrosis of 90% or more of the tumor is associated with an excellent prognosis ¹¹²⁾.

The following potential prognostic factors have been identified but have not been tested in large numbers of patients:

• HER-2/neu (c-erbB-2) expression. There are conflicting data concerning the prognostic significance of this human epidermal growth factor ¹¹³⁾.
• Tumor cell ploidy ¹¹⁴⁾.
• Specific chromosomal gains or losses ¹¹⁵⁾.
• Loss of heterozygosity of the RB gene ¹¹⁶⁾.
• Loss of heterozygosity of the p53 locus ¹¹⁷⁾.
• Increased expression of p-glycoprotein ¹¹⁸⁾. A prospective analysis of p-glycoprotein expression determined by immunohistochemistry failed to identify prognostic significance for newly diagnosed patients with osteosarcoma, although earlier studies suggested that overexpression of p-glycoprotein predicted poor outcome ¹¹⁹⁾.
• Time to definitive surgery. In a large series, a delay of 21 days or longer from the time of definitive surgery to the resumption of chemotherapy was an adverse prognostic factor ¹²⁰⁾.

What is neutropenia

Neutropenia is when you have a lower than normal number of neutrophils (a type of white blood cells) in your blood. While all white blood cells help your body fight infections, neutrophils play an essential role in immune defenses because they ingest, kill and digest invading microorganisms, including fungi and bacteria ¹⁾. Failure to carry out this role leads to immunodeficiency that is mainly characterized by the presence of recurrent infections ²⁾. You probably won’t know that you have neutropenia. People often only find out when they’ve had blood tests done for other reasons.

A single blood test showing low levels of neutrophils doesn’t necessarily mean you have neutropenia. These levels can vary from day to day, so if a blood test shows you have neutropenia, it needs to be repeated for confirmation.

Neutropenia can make you more vulnerable to infections. When neutropenia is severe, even the normal bacteria from your mouth and digestive tract can cause serious illness. You need to take special care to avoid infections when have neutropenia.

The normal count of neutrophils in the blood is between 1,500 and 5,500 neutrophils per microliter (1.5 x 10⁹/L and 5.5 x 10⁹/L) of blood. For children, the cell count indicating neutropenia varies with age. A neutrophil count below 1,000 neutrophils per microliter of blood (1.0 x 10⁹/L) is called neutropenia.

This degree of neutropenia can be “mild” (1.0 – 1.8 x 10⁹/L), “moderate” (0.5 – 1.0 x 10⁹/L), or “severe” (less than 0.5 x 10⁹/L). It should be emphasized, however, that the duration of neutropenia, the function of neutrophils and other host defenses, and the capacity of the bone marrow to respond also contribute considerably to the relative susceptibility of a patient to infection.

Some people have lower-than-average neutrophil counts, but not an increased risk of infection. In these situations their neutropenia isn’t a concern. Neutrophil counts less than 1,000 neutrophils per microliter (1.0 x 10⁹/L) — and especially counts of less than 500 neutrophils per microliter (0.5 – 1.0 x 10⁹/L) — are always considered to be neutropenia, where even the normal bacteria from your mouth and digestive tract can cause serious infections.

If you have neutropenia, you might have no symptoms at all. Some people get bacterial infections on different parts of the body like their skin, mouth area and gums, sinuses or internal organs such as their lungs. Such patients frequently demonstrate mucosal inflammation, particularly of the gingival and perirectal areas and often manifest cellulitis, abscesses, furunculosis, pneumonia or septicemia. Unlike normal individuals, infections in these individuals often lack the fluctuance, induration, and exudate that typically accompany a normal inflammatory response. While superficial infections cause substantial morbidity in these patients, deep-tissue infections of the sinuses, lungs, liver and blood pose the greatest risk. Resistant organisms caused by the repeated use of broad spectrum antibiotics often complicate treatment.

Acquired non-malignant neutropenia occurs much more commonly than chronic neutropenia. In children, the acute forms are most frequently seen in association with viral infection. Neutropenia in this setting usually develops over one to two days and can persist for up to a week without serious sequelae. Since concomitant diminution of other cell lines in this setting is unusual, evaluation for malignancy should be considered if the red cell or platelet compartment are also significantly decreased. In the seriously ill patient – particularly the neonate – sepsis can cause acute Neutropenia. Since such patients can deplete their neutrophil reserves during an overwhelming infection, granulocyte transfusions may be life-saving.

Neutropenia is usually found when your doctor orders tests for a condition you’re already experiencing. It’s rare for neutropenia to be discovered unexpectedly or by chance.

Talk to your doctor about what your test results mean. Neutropenia and results from other tests might indicate the cause of your illness. Or, your doctor may suggest other tests to further check your condition.

Because neutropenia makes you vulnerable to bacterial and fungal infections, your doctor will probably advise certain precautions. These often include wearing a face mask, avoiding anyone with a cold, and washing your hands regularly and thoroughly.

Neutropenia with decreased production with marrow hypoplasia can be primary and due to chronic benign neutropenia, cyclical neutropenia and other congenital and familial neutropenias. It can be secondary to cytotoxic drugs, aplastic anemia, leukemia, drug reactions, and infections. Neutropenia with increased destruction with marrow hyperplasia is due to hypersplenism and immune neutropenia. Secondary causes are the commonest, for example, neutropenia caused as a side effect of chemotherapy for malignancies. Congenital forms are rare and vary in severity, some of them are life-threatening conditions including leukocyte adhesion deficiency, Chediak-Higashi syndrome, hyper-IgE, recurrent infection syndrome, and chronic granulomatous disease ³⁾.

What are neutrophils

Neutrophils also known as neutrophilic granulocytes or polymorphonuclear leukocytes are a type of white blood cells (leukocytes) that normally make up the largest number of circulating white blood cells ⁴⁾. Neutrophils are considered to be the first line of defense during inflammation and infections. Neutrophils play a crucial role in the immune defense against bacterial and fungal pathogens, and they also participate in the development of the inflammatory reaction ⁵⁾. Neutrophils move into an area of damaged or infected tissue, where they engulf and destroy bacteria or sometimes fungi. Although neutrophils are mostly viewed as playing a beneficial role to the host, their improper activation may also lead to tissue damage during an autoimmune or exaggerated inflammatory reaction ⁶⁾.

Neutrophils participate in antimicrobial host defense both as the first line of innate immune defense and as effectors of adaptive immunity. Neutrophils are short-lived cells that usually die while performing their antimicrobial function.

A major wave of discoveries during the 1990s and early 2000s made immunologists begin to appreciate the amazing complexity and sophistication of neutrophil functions ⁷⁾. It became evident that neutrophils release cytokines and contribute to orchestrating the immune/inflammatory response ⁸⁾. A highly sophisticated machinery directing neutrophil migration ⁹⁾ and a surprising complexity of neutrophil granules ¹⁰⁾ also begun to emerge. Novel but controversial concepts about how neutrophils may fight microbes, including possible regulation of granule enzyme function by ion fluxes ¹¹⁾ and formation of neutrophil extracellular traps (NETs) ¹²⁾ were also proposed during that period. Both mechanisms have been subject to intense debate. Nevertheless, all those studies indicated that neutrophils use highly sophisticated and complex mechanisms to perform their role in immune defense and inflammation and led to improved and refined models of neutrophil biology ¹³⁾ (Figure 1).

Key points

• The neutrophil is one of the body’s main cellular mediators of the destruction of microorganisms, and inevitably damages cells and tissues of the host. Neutrophil-mediated tissue destruction is most often a life-saving process, and the host relies on tissue injury as one of the main sources of information that launches inflammation and immunity.
• Large numbers of immature forms of neutrophils, called neutrophilic band cells, are produced by the bone marrow when the demand is high.
• Neutrophils make important contributions to the recruitment, activation and programming of dendritic cells and macrophages. In turn, the adaptive immune system controls the rate of neutrophil production in the bone marrow.
• Neutrophils have important roles in healing wounds, including sterilization of microorganisms, generation of signals that slow the rate of accumulation of more neutrophils, and instigation of a macrophage-based programme that switches the state of damaged epithelium from pro-inflammatory and nonreplicative, to anti-inflammatory and replicative.
• Neutrophil production is coordinated through cytokine production by adaptive immune cells.
• Neutrophil recruitment to sites of infection involves unique molecular interactions in different tissues.
• Recognition of pathogens by neutrophils involves coordination between a repertoire of cellular receptors.
• Killing of pathogens is achieved through the production of toxic metabolites and the release of nuclear contents.
• Heritable disorders of neutrophils provide key insights into molecular mechanisms of neutrophil function.
• Neutrophils play a central role in coordinating the response of other immune effector cells.
• Pathologic interactions between adaptive immune cells and neutrophils are a major contributor to many autoimmune and inflammatory disease states.
• Neutrophils play both positive and negative roles in cancer progression.
• Neutrophils are short-lived cells that die within a limited time after entering the circulation ¹⁴⁾. In the absence of infection or inflammation, they die by a spontaneous apoptosis program ¹⁵⁾, likely within 1 day (although some investigators propose this time to be up to 5 days) ¹⁶⁾. Inflammatory signals are capable of prolonging the lifespan of the cells by several days, during which they release inflammatory mediators and contribute to the orchestration of the inflammatory response ¹⁷⁾.
• Accumulating data showed that neutrophils had a variety of important biological functions in both innate and adaptive immunities, far beyond cytotoxicity against pathogens. Neutrophils can differentially switch phenotypes and display distinct subpopulations under different microenvironments. Neutrophils can produce a large variety of cytokines and chemokines upon stimulation. Furthermore, neutrophils directly interact with dendritic cells (DCs), macrophages, natural killer cells, T cells, and B cells so as to either potentiate or down-modulate both innate and adaptive immunity. In the present review, we summarize the recent progress on the functional plasticity and the regulatory ability on immunity of neutrophils in physiological and pathological situations.
• New pathways of tumor-necrosis factor (TNF) signal transduction in neutrophils are being characterized that open up a new way to think of anti-inflammatory therapy, for example, pathways involving tumor-necrosis factor (TNF)-induced increases in intracellular Ca2+ and the ensuing activation of a non-transmembrane form of adenylyl cyclase, termed soluble adenylyl cyclase.

In addition, neutrophils are also found infiltrating many types of tumors ¹⁸⁾. Tumor-associated neutrophils have relevant roles in malignant disease. Indeed neutrophils may be potent antitumor effector cells. However, increasing clinical evidence shows tumor-associated neutrophils correlate with poor prognosis. The tumor microenvironment controls neutrophil recruitment and in turn tumor-associated neutrophils help tumor progression. Hence, tumor-associated neutrophils can be beneficial or detrimental to the host ¹⁹⁾.

Neutrophils functions

Neutrophils are terminally differentiated cells that develop in the bone marrow where they are also stored for release into the circulation. During their maturation, neutrophils develop several intracellular compartments (secretory granules and vesicles) that store proteins critical for the antimicrobial and proinflammatory missions of the cell ²⁰⁾. Once released into the circulation, neutrophils begin to seek signs of infection and inflammation which lead to a series of events culminating in the migration of neutrophils through the vessel wall and inside the tissue to the site of microbial invasion ²¹⁾ (see Figure 1).

When encountering infectious particles, neutrophils begin a professional antimicrobial killing program. The infectious particle will be phagocytosed ²²⁾ and various noxious agents, including reactive oxygen species generated through the activity of the NADPH oxidase ²³⁾, and the contents of intracellular granules ²⁴⁾ are then released into the phagosome, resulting in killing and digestion of the microorganisms (see Figure 1). In cell biology, phagocytosis is the process by which a cell – for example a neutrophil – engulfs a solid particle to form an internal compartment known as a phagosome.

Besides the well-established role of phagocytosis, two additional mechanisms contributing to neutrophil-mediated antimicrobial responses have been proposed during the early 2000s, both of them triggering intensive scrutiny and debate from the scientific community. Segal et al. ²⁵⁾ proposed an interesting molecular interplay whereby ion fluxes triggered by the NADPH oxidase would promote the antimicrobial function of granule proteins. Though many components of the proposed mechanism (such as the electrogenicity of the NADPH oxidase [see Figure 1 inset] providing driving force for other ion currents) are generally accepted, it is still debated whether and to what extent ion fluxes that compensate for the activity of the NADPH oxidase contribute to the antibacterial effects of granule enzymes ²⁶⁾. Another interesting and similarly provocative idea was that, in addition to intraphagosomal killing, neutrophils may also be able to expel their nuclear content (including DNA) complexed with granule proteins into the extracellular space and that this complex, neutrophil extracellular traps (NETs), may inhibit microbial growth without phagocytosis of the pathogen ²⁷⁾. Though neutrophil-derived extracellular DNA has long been known to be present at the site of infection (in part as a component of pus formation) and neutrophil extracellular trap (NET) formation has recently been directly visualized during bacterial infection in vivo ²⁸⁾, the contribution of neutrophil extracellular trap (NET) formation to antibacterial host defense and killing is still under intensive debate ²⁹⁾.

Neutrophils are short-lived cells that die within a limited time after entering the circulation ³⁰⁾. In the absence of infection or inflammation, they die by a spontaneous apoptosis program ³¹⁾, likely within 1 day (although some investigators propose this time to be up to 5 days) ³²⁾. Inflammatory signals are capable of prolonging the lifespan of the cells by several days, during which they release inflammatory mediators and contribute to the orchestration of the inflammatory response ³³⁾. However, even under those conditions, neutrophils will soon die by apoptosis (or, possibly, NETosis), contributing to pus formation inside infected tissues. Once neutrophils die, another program for removal of dead neutrophils by macrophages is initiated ³⁴⁾. Parallel to the inflammatory response, biochemical and transcriptional changes leading to the resolution of the inflammation begin ³⁵⁾, and this is further promoted by engulfment of the corpses of dead neutrophils by macrophages ³⁶⁾.

Figure 1. Neutrophils function

Footnotes: After migrating to the site of inflammation, neutrophils (PMN) phagocytose and digest the invading microbes; release neutrophil extracellular traps (NETs), which likely trap bacteria; and produce cytokines, which contribute to the inflammatory reaction. Once infection is cleared, neutrophils die by apoptosis and trigger an active program to resolve inflammation.

Inset: Cytotoxic functions of neutrophils.

Pathogen killing inside the phagosome occurs by reactive oxygen species (ROS) generated by the NADPH oxidase, as well as by granule enzymes released from intracellular granules. The NADPH oxidase also induces depolarization of the phagosomal membrane, which may be required for providing optimal environment inside the phagosome.

[Source ³⁷⁾]

Figure 2. Blood composition

Blood is a complex mixture of formed elements in a liquid extracellular matrix, called blood plasma. Note that water and proteins account for 99% of the blood plasma.

Note: Blood consists of a liquid portion called plasma and a solid portion (the formed elements) that includes red blood cells, white blood cells, and platelets. When blood components are separated by centrifugation, the white blood cells and platelets form a thin layer, called the “buffy coat,” between the plasma and the red blood cells, which accounts for about 1% of the total blood volume. Blood cells and platelets can be seen under a light microscope when a blood sample is smeared onto a glass slide.

Figure 3. Bone marrow anatomy

Anatomy of the bone. The bone is made up of compact bone, spongy bone, and bone marrow. Compact bone makes up the outer layer of the bone. Spongy bone is found mostly at the ends of bones and contains red marrow. Bone marrow is found in the center of most bones and has many blood vessels. There are two types of bone marrow: red and yellow. Red marrow contains blood stem cells that can become red blood cells, white blood cells, or platelets. Yellow marrow is made mostly of fat.

Figure 4. White blood cells development. A blood stem cell goes through several steps to become a red blood cell, platelet, or white blood cell

Figure 5. White blood cells development

Figure 6. White blood cells

What is neutrophils absolute count

You might hear your doctor or nurse talk about your absolute neutrophil count or ANC. This is the number of neutrophils you have in a certain amount of blood. Your health care team will use your absolute neutrophil count (ANC) to get an idea of how well your immune system might work during treatment. You might want to keep track of your absolute neutrophil count (ANC) so you’ll know when you have a higher risk of getting an infection.

Some labs put this number on your complete blood count (CBC) report, but it isn’t always labeled “ANC,” so you may need to ask your doctor or nurse for help finding it. Sometimes the lab will only report different types of neutrophils as a percentage of white blood cells, and then your health care team will calculate your absolute neutrophil count (ANC). You can also calculate it yourself.

A routine blood smear identifies the five types of white blood cells—neutrophils, lymphocytes, monocytes, eosinophils, and basophils. Neutrophils make up about 55% to 70% of the total white blood cell count. Their primary function is phagocytosis—a process by which they engulf and digest microorganisms and cell fragments.

Acute bacterial infection and trauma stimulate neutrophil production, which elevates the white blood cell count. Significant stimulation of neutrophil production causes immature neutrophil forms, called bands or stab cells, to enter the circulation.

Absolute neutrophil count is an essential monitoring parameter for cancer patients at risk for bone marrow suppression caused by chemotherapy, radiation therapy, or bone marrow transplant. If your patient’s absolute neutrophil count is abnormally low, be sure to practice meticulous hand hygiene—the single most important way to prevent infection in these patients.

Normal and abnormal absolute neutrophil count values

A healthy person has an absolute neutrophil count (ANC) between 2,500 and 6,000/mm³ or per microliter.

The absolute neutrophil count is found by multiplying the white blood cell count by the percent of neutrophils in the blood. For instance, if the white blood cell count is 8,000/mm³ and 50% of the white blood cells are neutrophils, the absolute neutrophil count is 4,000 (8,000 × 0.50 = 4,000).

When the absolute neutrophil count drops below 1,000/mm³ it is called neutropenia. Neutropenia refers to an abnormally low absolute neutrophil count. Your doctor will watch your absolute neutrophil count closely because the risk of infection is much higher when the absolute neutrophil count is below 500. A value above 1,000/mm³ usually means it’s safe to continue chemotherapy. On the other hand, a value below 1,000/mm³ sharply increases the risk of infection.

Figuring out your absolute neutrophil count (ANC)

The numbers for your absolute neutrophil count (ANC) are taken from the results of a blood test called the differential white blood cell (WBC) count. You can ask about the results of your blood tests or get copies of your test results from your doctor or nurse.

To find out your absolute neutrophil count (ANC), multiply the percentage of neutrophils by the total number of white blood cells. Neutrophils are sometimes called segs or polys, and young neutrophils may be called bands on your lab report. If bands are listed as a percentage of white blood cells, add them to the neutrophils before multiplying.

You can figure out your white blood cell using this formula:

• [(% of neutrophils + % of bands) ÷ 100] × white blood cell count = absolute neutrophil count (ANC)
  

So, for example, if a patient’s white blood cell count is 2,000, with 65% neutrophils and 5% bands, then the ANC is 1,400, which is calculated like this:

• ANC = [(65 + 5) ÷ 100] × 2,000
• ANC = (70 ÷ 100) × 2,000
• ANC = 0.7 × 2,000 = 1,400

An absolute neutrophil count (ANC) of less than 1,000 means that you have neutropenia (a low number of neutrophils) and your immune system is weak. Ask your doctor or nurse to tell you exactly what your numbers mean.

The lower the absolute neutrophil count (ANC) drops and the longer it stays low, the higher your risk of getting a serious infection. If the absolute neutrophil count (ANC) drops below 500 for a few days, you are at a very high risk of getting an infection. If your absolute neutrophil count (ANC) is 100 or less for more than a week, your risk of serious infection is extremely high.

In a person with a healthy immune system, the usual signs of infection are fever, pus, pain, swelling, and redness. As the absolute neutrophil count (ANC) gets lower, many of these signs may not show up when an infection starts. This is because these signs are caused by neutrophils fighting off germs, and you don’t have enough neutrophils to produce the signs. This can make it hard to know if you have an infection. The good thing is that another white blood cell (WBC), called the monocyte, can still cause fever in the person who has neutropenia. In people with severe neutropenia, a fever may be the only sign of an infection.

If your absolute neutrophil count (ANC) is 1,000 or lower and you have a fever of 100.5° F (38° C) or higher when taken by mouth, your doctor will likely assume that you have an infection. Antibiotic treatment is usually started right away, often before the cause of the infection can even be found. Until they can pinpoint the exact bug, doctors learn what they can about the infection to narrow down the treatment options. But they still look for the exact cause so that they can choose the treatment that’s most likely to work – even if it means changing to different antibiotics than what they started with.

Uses of the absolute neutrophil count

Knowing a patient’s absolute neutrophil count has several advantages:

• It reflects the patient’s immunologic status in response to chemotherapy. Myelosuppressive chemotherapy suppresses white blood cell (and thus neutrophil) production, raising the risk of severe infection. A low absolute neutrophil count may indicate the need to delay the next chemotherapy dose or to reduce the dosage.
• The absolute neutrophil count value helps predict subsequent neutro­penic events (such as fever) after the first chemo­therapy cycle by providing a more accurate picture of immunologic status than the neutrophil or white blood cell count alone.
• It helps the physician determine whether to initiate treatment with growth factors, antibiotics, and other protective measures to decrease the risk of neutro­penic complications. For example, administering filgrastim (recombinant methionyl human granulocyte colony-stimulating factor) can shorten neutropenia duration and reduce the risk of febrile neutropenia. This in turn increases the chance that full-dose chemotherapy can be given on time.
• For a hospitalized patient, a low absolute neutrophil count may indicate the need for protective isolation to guard against exposure to infection. For an outpatient, it may indicate the need to avoid crowds and people with colds, runny noses, or influenza.

How to calculate absolute neutrophil count

You can calculate your patient’s absolute neutrophil count in one of two ways.

Figure 7. How to calculate absolute neutrophil count (ANC)

Neutropenia causes

Numerous factors may cause neutropenia through destruction, decreased production or abnormal storage of neutrophils.

Cancer and cancer treatments

Cancer chemotherapy is a common cause of neutropenia. In addition to killing cancer cells, chemotherapy can also destroy neutrophils and other healthy cells.

• Leukemia
• Chemotherapy
• Radiation therapy

Drugs

• Medications used to treat overactive thyroid, such as methimazole (Tapazole) and propylthiouracil
• Certain antibiotics, including vancomycin (Vancocin), penicillin G and oxacillin
• Antiviral drugs, such as ganciclovir (Cytovene) and valganciclovir (Valcyte)
• Anti-inflammatory medication for conditions such as ulcerative colitis or rheumatoid arthritis, including sulfasalazine (Azulfidine)
• Some antipsychotic medications, such as clozapine (Clozaril, Fazaclo, others) and chlorpromazine
• Drugs used to treat irregular heart rhythms, including quinidine and procainamide
• Levamisole — a veterinary drug that’s not approved for human use in the United States, but may be mixed in with cocaine

Infections

• Chickenpox
• Epstein-Barr
• Hepatitis A
• Hepatitis B
• Hepatitis C
• HIV/AIDS
• Measles
• Salmonella infection
• Sepsis (an overwhelming bloodstream infection)

Autoimmune diseases

• Granulomatosis with polyangiitis (formerly called Wegener’s granulomatosis)
• Lupus
• Rheumatoid arthritis

Myeloproliferative neoplasms or myeloproliferative disorders

• Aplastic anemia
• Myelodysplastic syndromes
• Myelofibrosis

Additional causes

• Conditions present at birth, such as Kostmann’s syndrome (a disorder involving low production of neutrophils)
• Unknown reasons, called chronic idiopathic neutropenia
• Vitamin deficiencies
• Abnormalities of the spleen

People can have neutropenia without an increased risk of infection. This is known as benign neutropenia.

Neutropenia prevention

You cannot prevent neutropenia from occurring, but you can decrease your risk of getting an infection while your white blood cell count is low.

Tips to prevent an infection:

• Wash your hands often.
• Clean your teeth and gums with a soft toothbrush, and if your doctor or nurse recommends one, use a mouthwash to prevent mouth sores.
• Shower or bathe daily and use an unscented lotion to prevent your skin from becoming dry and cracked.
• Do not share food, drink cups, utensils or other personal items, such as toothbrushes.
• Try to avoid crowded places and contact with people who are sick.
• Cook meat and eggs all the way through to kill any germs.
• Carefully wash raw fruits and vegetables.
• Try and keep all your household surfaces clean.
• Protect your skin from direct contact with pet bodily waste (urine or faeces) by wearing vinyl or household cleaning gloves when cleaning up after your pet.
• Wash your hands immediately afterwards.
• Use gloves for gardening.
• Get your flu vaccination every year.

Neutropenia symptoms

If you have neutropenia, you might have no symptoms at all. Some people get bacterial infections on different parts of the body like their skin, mouth area and gums, sinuses or internal organs such as their lungs.

Neutropenia is usually found when your doctor orders tests for a condition you’re already experiencing. It’s rare for neutropenia to be discovered unexpectedly or by chance.

Hsieh and collaborators reported that in the United States, the prevalence of neutropenia was 0.38% among Mexican-Americans, 0.79% among whites, and 4.5% among black participants ³⁸⁾. Weycker and collaborators ³⁹⁾ reported that the risk of febrile neutropenia during the chemotherapy regimen course for treating solid tumor was 16.8%. Severe neutropenia was present in 1 of every 2 patients with lymphoma receiving chemotherapy with a higher risk of febrile neutropenia, and it was found in approximately 1 of every 10 breast cancer patients in Spain ⁴⁰⁾.

Since having neutropenia puts you at increased risk of infection, you may have one or more of these symptoms:

• Fever (temperature over 100.4 °F [38°C])
• Chills or shaking
• Unusual sweating including night sweat
• Sore throat
• Mouth ulcers
• Burning feeling when passing urine; more frequent urination
• Diarrhea.

If you have one or more of the symptoms above, contact your doctor immediately.

People with neutropenia who develop an infection can become seriously ill very quickly. In some cases, this can be life-threatening. Some people who have neutropenia are more at risk of becoming seriously ill than other people. This may be because they have other illnesses as well as their cancer. They may have a more severe infection.

Neutropenia complications

• Recurrent and fatal bacterial and fungal infections ⁴¹⁾
• Bacteremia
• Septic shock
• Premature death
• Failure to thrive
• Protein-energy malnutrition
• Multi-organ failure

Neutropenia diagnosis

In neutropenia there is a history of ⁴²⁾:

• Recurrent infections
• Infections caused by rare bacteria and fungi
• Opportunistic infections
• Frequent use of antibiotics and antifungals

The physical findings include ⁴³⁾:

• Delayed separation of umbilical cord
• Skin infections
• Gingivitis
• Deep abscesses
• Peritonitis
• Osteomyelitis
• Lung abscesses
• Pneumatoceles
• Sinus and lung infections, e.g., pneumonia
• Otitis media
• Meningitis
• Septicemia
• Arthritis
• Bacteremia
• Fever
• Coarse facial features
• Mucocutaneous candidiasis
• Cough
• Malaise
• Intestinal malabsorption
• Bronchiectasis
• Recurrent tonsillitis
• Extensive cutaneous bacterial (Staphylococcal) infections
• Sore throat
• Purulent conjunctivitis
• Granuloma with catalase-positive organisms
• Skin abnormalities, e.g., pyodermitis
• Splenomegaly
• Diarrhea
• Recurrent abscess
• Aphthous stomatitis
• Urinary sepsis
• Vasculitis
• Poor wound healing

The immunological investigation of a patient with neutropenia includes the assessment of immunoglobulins, complement system, and phagocytes ⁴⁴⁾.

Quantitative Serum Immunoglobulins

• IgG
• IgM
• IgA
• IgE

Blood Lymphocyte Subpopulations

• B lymphocytes (CD19 and CD20)

Phagocytic Function

Nitroblue tetrazolium (NBT) test (before and after stimulation with endotoxin)

• Unstimulated
• Stimulated

Neutrophil mobility

• In medium alone
• In presence of chemoattractant

Complement System Evaluation

Measurement of individuals components by immunoprecipitation tests, ELISA, or Western blotting

• C3 serum levels
• C4 serum levels

Hemolytic assays

• CH50

Complement system functional studies

• Classical pathway assay (using IgM on a microtiter plate)
• Alternative pathway assay (using LPS on a microtiter plate)
• Mannose pathway assay (using mannose on a microtiter plate)

Microbiological studies

• Blood culture
• Urine culture
• Stool culture
• Sputum culture
• Cerebrospinal fluid (culture, chemistry, and histopathology)

Other investigations of immunodeficiency disorders

• Complete blood cell count
• Bone marrow biopsy
• Histopathological studies
• Blood chemistry
• Tumoral markers
• Levels of cytokines (granulocyte-colony stimulating factor)
• Chest x-ray
• Diagnostic ultrasound
• CT scan
• Fluorescent in situ hybridization (FISH)
• DNA testing (for most congenital disorders)

Neutropenia treatment

Application of granulocyte-colony stimulating factor (G-CSF) can improve neutrophil functions and number ⁴⁵⁾. Prophylactic use of antibiotics and antifungals is reserved for some forms of alteration in neutrophil function such as chronic granulomatous disease) ⁴⁶⁾. The utilization of antimicrobials is compulsory if recurrent infections exist. Interferon-gamma has been successfully used to improve the quality of life of the patient suffering from neutropenia. Allogenic bone marrow transplantation from an HLA-matched related donor can cure chronic granulomatous disease but has a high mortality rate ⁴⁷⁾, and gene therapy is also a therapeutic option for treating disorders with neutropenia. Furthermore, intravenous immunoglobulins can be another option in the management of these disorders ⁴⁸⁾.

Neutropenia prognosis

The prognosis of neutropenia disorders base on the cause and organs involved. Chronic granulomatous disease has a better prognosis if allogenic bone marrow transplantation can successfully achieve. Neutropenia due to chemotherapy or drugs may cause remission once the treatment is over. Some primary defects of neutrophil functions affect the prognosis, where devastating fatal diseases can lead to death in young age ⁴⁹⁾.

Febrile neutropenia

Febrile neutropenia or neutropenic fever is defined as a single oral temperature of greater than or equal to 101 °F (38.3°C) or a temperature greater than or equal to 100.4 °F (38 °C) for at least an hour, with an absolute neutrophilic count (ANC) of less than 1,500 cells/microliter (1.5 x 10⁹/L) of blood ⁵⁰⁾. In severe neutropenia, the absolute neutrophilic count (ANC) is less than 500 per microliter (<0.5 x 10⁹/L) or ANC that is expected to decrease below 500 cells/microL (<0.5 x 10⁹/L) in the next 2 hours. In profound neutropenia, the ANC is less than 100 cells/microliter (0.1 x 10⁹/L). To calculate absolute neutrophilic count (ANC), multiply the total white blood cell (WBC) count by the percentage of polymorphonuclear cells and band neutrophils (see ANC calculation and formula above) ⁵¹⁾.

Febrile neutropenia is the most common and serious complication associated with hematopoietic cancers or with patients receiving chemotherapeutic regimens for cancer ⁵²⁾. Febrile neutropenia occurs when a neutropenic patient encounters an infectious pathogen. In this immunocompromised state, patients lose or have weakened immunity to fend off infections. The host barriers, such as the mucosal lining of the gastrointestinal tract or sinuses, may be damaged leading the host, open to invasion from an infectious pathogen ⁵³⁾. About 1% of patients undergoing chemotherapy and radiation experience this complication ⁵⁴⁾.

Despite major advances in prevention and treatment, febrile neutropenia remains one of the most frequent and serious complications of cancer chemotherapy ⁵⁵⁾. Febrile neutropenia is a major cause of morbidity, healthcare resource use and compromised treatment efficacy resulting from delays and dose reductions of cancer chemotherapy. Mortality from febrile neutropenia has diminished steadily, but remains significant.

The specific frequency of neutropenia is unknown; It could be estimated to be 1.0 to 3.4 cases per million population per year ⁵⁶⁾. Neutropenia was particularly associated with HIV infection, acute leukemias, and myelodysplastic syndromes. Drug-induced neutropenia has an incidence of one case per million persons per year. About, 50% of patients with febrile neutropenia will develop an infection, of which 20% with profound neutropenia will observe bacteremia ⁵⁷⁾.

Most standard-dose cancer chemotherapy regimens are associated with 6–8 days of neutropenia, and febrile neutropenia is observed in ∼8 cases per 1000 patients receiving cancer cancer chemotherapy ⁵⁸⁾. Febrile neutropenia is responsible for considerable morbidity as 20%–30% of patients present complications that require in-hospital management, with an overall in-hospital mortality of ∼10%. The mean cost per hospitalisation in Western countries is ∼€13,500 (US$15 000).

There is a clear relationship between the severity of neutropenia (which directly influences the incidence of febrile neutropenia) and the intensity of cancer chemotherapy. Currently, the different regimens are classified as producing a high risk (>20%), an intermediate risk (10%–20%) or a low risk (<10%) of febrile neutropenia.

It has been shown that several factors, other than cancer chemotherapy itself, are responsible for increasing the risk of febrile neutropenia and its complications. Among them, age plays a major role with older patients having a higher risk of febrile neutropenia following cancer chemotherapy, with worse morbidity and mortality rates. Other factors having a similar role are as follows: The risk of febrile neutropenia and its complications increases when one or several co-morbidities are present in the patient. These considerations will be instrumental in deciding whether a cancer chemotherapy-treated patient should receive primary prophylaxis to decrease the potential risk of febrile neutropenia.

• advanced disease,
• history of prior febrile neutropenia,
• no antibiotic prophylaxis or granulocyte colony-stimulating factor (G-CSF) use,
• mucositis,
• poor performance status and/or
• cardiovascular disease.

In the case of febrile neutropenia, prognosis is worst in patients with proven bacteraemia, with mortality rates of 18% in Gram-negative and 5% in Gram-positive bacteremia [for bacteremias due to coagulase-negative Staphylococcus only, no attributable mortality has been reported] ⁵⁹⁾. The presence of a focal site of presumed infection (e.g. pneumonia, abscess, cellulitis) also makes the outcome worse. Mortality varies according to the Multinational Association of Supportive Care in Cancer (MASCC) prognostic index (see Table 1 below): lower than 5% if the MASCC score is ≥21, but possibly as high as 40% if the MASCC score is <15 ⁶⁰⁾.

Febrile neutropenia causes

In the majority of cases, the infectious cause is unable to be determined and gets marked as fever of unknown origin (FUO). The definition of fever of unknown origin (FUO) is neutropenic cases with a fever greater than 100.94 °F (38.3°C), without any clinically or microbiologically defined infection ⁶¹⁾. Documented infections only comprise approximately 30% of cases. However, infections are the primary cause of morbidity and mortality in patients with cancer who present with fever and neutropenia ⁶²⁾. Majority of infections are bacterial, but viral or fungal etiology is possible ⁶³⁾. Common bacterial pathogens include gram-positive bacteria infections such as Staphylococcus, Streptococcus and Enterococcus species ⁶⁴⁾. Drug-resistant organisms including Pseudomonas aeruginosa, Acinetobacter species, Stenotrophomonas maltophilia, Escherichia coli and Klebsiella species have also been identified as infectious agents.

Febrile neutropenia diagnosis

A detailed history of the patients presenting illness, chemotherapy treatment, medication use, previous history of infections especially with bacterial resistant organisms and presence of allergies should be noted to guide your therapy ⁶⁵⁾. Signs of infection may require assessment; Pain and tenderness may be the only indicators of infection. Significant risk factors for the development of febrile neutropenia include older age, comorbidities, the specific type of cancer, and the type and number of myelosuppressive chemotherapy agents in use ⁶⁶⁾.

Lab tests

Lab tests should be ordered; complete blood count (CBC) to determine patients’ neutropenic level; blood, urinanalysis and throat cultures are needed to determine the source of infection. Two sets of blood cultures should be obtained from a peripheral vein and any venous catheters as well as specimens for testing from any sites of infection, before the immediate administration of empirical broad-spectrum antimicrobial therapy. Urinary tract infections should be suspected in asymptomatic patients with a history of such infections ⁶⁷⁾. If diarrhea is present a sample may be checked. If the patients have any respiratory symptoms, a chest X-ray is necessary.

Two widely used assessment tools, The Multinational Association for Supportive Care in Cancer (MASCC), and The Clinical Index of the Stable Febrile Neutropenia (CISNE) can be part of the patient interview. These tools can help to risk-stratify patients into high risk and low-risk neutropenic fever.

The Multinational Association for Supportive Care in Cancer (MASCC) was created the assess the risk of serious complications in patients with neutropenic fever. The Multinational Association for Supportive Care in Cancer (MASCC) index has a max score of 26. Patients with a score greater than 21 are considered low risk and patients less than 21 are high risk ⁶⁸⁾.

Multinational Association for Supportive Care in Cancer (MASCC) Scoring Index

Table 1. Multinational Association for Supportive Care in Cancer (MASCC) febrile neutropaenia risk index

Characteristics	Score
Burden of illness: no or mild symptoms	5
Burden of illness: moderate symptoms	3
Burden of illness: severe symptoms	0
No hypotension (systolic BP > 90 mmHg)	5
No chronic obstructive pulmonary disease	4
Solid tumour/lymphoma with no previous fungal infection	4
No dehydration	3
Outpatient status (at onset of fever)	3
Age <60 years	2

Footnote: BP = blood pressure

Characteristic/Score

• The burden of illness: no or mild symptoms/5
• The burden of illness: none or mild/5
• The burden of illness: moderate symptoms/3
• The burden of illness: severe symptoms/0
• No hypotension (systolic BP greater than 90mmHg)/5
• No chronic obstructive pulmonary disease/4

Type of Cancer

• Solid tumor/4
• Lymphoma with previous fungal infection/4
• Hematologic with previous fungal infection/4
• No dehydration/4
• Outpatient status (at the onset of fever)/3
• Age less than 60 years/2

Patients with scores ≥21 are at low risk of complications. Points attributed to the variable ‘burden of illness’ are not cumulative. The maximum theoretical score is therefore 26 ⁶⁹⁾.

The Clinical Index of Stable Febrile Neutropenia Score

A more specific scale for classification of low-risk patients is the Clinical Index of the Stable Febrile Neutropenia (CISNE) and may be more useful in the Emergency Department setting ⁷⁰⁾. One of the components of the scale is the Eastern Cooperative Oncology Group (ECOG) Performance Status, which helps determines the patient’s functional status as a surrogate for the patient’s ability to undergo therapies in serious illnesses.

The Clinical Index of Stable Febrile Neutropenia Score

Characteristics/Score

• Eastern Cooperative Oncology Group (ECOG) performance status (greater than 2)/2
• COPD/1
• Stree-induced hyperglycemia/2
• Chronic cardiovascular disease/1
• Monocytes less than 200 per mcL/1
• Grade greater than or equal to 2 mucositis/1
• Interpretation

CISNE/Recommendation

• 0-2/Consider outpatient management with oral antibiotics
• Greater than or equal to 3/Inpatient management

Febrile neutropenia treatment

In low-risk patients, oral empiric therapy with a fluoroquinolone plus amoxicillin/clavulanate is recommended in the outpatient setting ⁷¹⁾. Clindamycin can be used for those with penicillin allergy. If the patient remains febrile for 48 to 72 hours, the patient will require admission ⁷²⁾.

For high-risk patients presenting with neutropenic fever, an intravenous antibiotic therapy should be given within 1 hour after triage and be monitored more than 4 hours before discharge. The Infectious Disease Society of America (IDSA) recommends monotherapy with antipseudomonal beta-lactam agents such as cefepime, carbapenems or Zosyn ⁷³⁾. Vancomycin is not recommended for initial therapy but should be considered if suspecting catheter-related infection, skin or soft tissue infections pneumonia or hemodynamic instability ⁷⁴⁾. If patients do not respond to treatments, coverage should be expanded to include resistant species ⁷⁵⁾:

• Methicillin-resistant Staphylococcus aureus (MRSA): vancomycin, linezolid, and daptomycin
• Vancomycin-resistant enterococci (VRE): linezolid and daptomycin
• Extended Spectrum Beta-Lactamase (ESBL): carbapenems
• Klebsiella pneumonia: carbapenems, polymyxin, colistin, or tigecycline

Recommendation for prevention of infection in neutropenic patients:

• Fluoroquinolones as prophylaxis for patients who are high risk
• Antifungal prophylaxis with an oral triazole with patients with profound neutropenia
• Trimethoprim/sulfamethoxazole (TMP-SMX) is the recommended treatment for patients receiving chemotherapy regimens associated with greater than 3.5% risk for pneumonia from Pneumocystis jirovecii
• Yearly influenza vaccination is recommended for all patients receiving chemotherapy
• Treatment with a nucleoside reverse transcription inhibitor is recommended for patients who are at high risk of hepatitis B virus reactivation
• Herpes simplex virus- seropositive patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT) or leukemia induction therapy should receive prophylaxis

In National Comprehensive Cancer Network guidelines, it is recommended that patients that are at a high risk of febrile neutropenia can benefit from G-CSFs ⁷⁶⁾.

Daily follow-up and assessment of response

The frequency of clinical assessment is determined by severity but may be required every 2–4 hours in cases needing resuscitation. Daily assessment of fever trends, bone marrow and renal function is indicated until the patient is afebrile and has an ANC of ≥500 neutrophils per microliter (≥0.5 x 10⁹/L) of blood (Figure 8) for 24 hours ⁷⁷⁾. Repeated imaging may be required in patients with persistent pyrexia.

If the patient is afebrile and has an ANC of ≥500 neutrophils per microliter (≥0.5 x 10⁹/L) of blood at 48 hours, has low risk and no cause of infection has been found, consider changing to oral antibiotics. If the patient is at high risk with no cause found and is on dual therapy, aminoglycoside may be discontinued. When the cause is found, continue on appropriate specific therapy ⁷⁸⁾.

If the patient is still febrile at 48 hours, but clinically stable, initial antibacterial therapy should be continued. If the patient is clinically unstable, antibacterial therapy should be rotated or broadened if clinical developments justify this. Some haematology units will add a glycopeptide to the regimen, while other centres will change the regimen to imipenem or meropenem and a glycopeptide. This group of patients with persistent fever is at a high risk of serious complications, and prompt advice from an ID physician or clinical microbiologist should be sought. Unusual infections should be considered, particularly in the context of a rising C-reactive protein, with a view to proceeding to imaging of the chest and upper abdomen, to exclude probable fungal or yeast infection, or abscesses. When the pyrexia lasts for >4–6 days, empirical initiation of antifungal therapy may be needed ⁷⁹⁾.

Duration of therapy

If the ANC is ≥500 neutrophils per microliter (≥0.5 x 10⁹/L) of blood, the patient is asymptomatic and has been afebrile for 48 hours and blood cultures are negative, antibacterials can be discontinued ⁸⁰⁾.

If the ANC is ≤500 neutrophils per microliter (≤0.5 x 10⁹/L) of blood, the patient has suffered no complications and has been afebrile for 5–7 days, antibacterials can be discontinued except in certain high-risk cases with acute leukaemia and following high-dose cancer chemotherapy when antibacterials are often continued for up to 10 days, or until the ANC is ≥500 neutrophils per microliter (≥0.5 x 10⁹/L) of blood ⁸¹⁾.

Patients with persistent fever despite neutrophil recovery should be assessed by an infectious disease physician or clinical microbiologist and antifungal therapy considered ⁸²⁾.

An overall algorithm for the assessment of response and subsequent management is proposed in Figure 8.

Figure 8. Febrile neutropenia assessment of response and subsequent management

[Source ⁸³⁾ ]

Febrile neutropenia guidelines

Key recommendations for the management of febrile neutropenia ⁸⁴⁾

• Febrile neutropenia is observed in ±1% of patients receiving cancer chemotherapy; it is associated with considerable morbidity (20%–30%) and mortality (10%)
• Febrile neutropenia can be effectively prevented by the use of granulocyte colony-stimulating factors (G-CSFs); it is recommended to use these agents in patients receiving chemotherapies with a >20% risk of developing febrile neutropenia and in those having serious co-morbidities and/or aged >60 years
• Patients with febrile neutropenia should be assessed for the risk of complications using a validated predictive tool, such as the Multinational Association of Supportive Care in Cancer (MASCC) score
• Patients with febrile neutropenia at a low risk of complications can often be treated with oral antibiotics and possibly as outpatients, if adequate follow-up is available
• Patients with febrile neutropenia at a high risk of complications should be hospitalised and treated without delay with broad spectrum antibiotics; these patients should be closely monitored for instability (pre-shock)

Specific indications for alternative therapy

Apart from the standard treatment with broad-spectrum antibacterial agents, there are a number of situations, in clinical practice, that require a specific regimen. The duration of treatment may vary and local antibacterial guidelines should be followed in these circumstances.

Central I.V. catheters

If a patient has an I.V. catheter, catheter-related infection (CRI) should be suspected, and blood must be cultured from the catheter and peripherally to measure the differential time to positivity (DTTP), which is the difference in time between positivity of results between catheter culture and peripheral blood culture. A differential time to positivity of ±2 h is a highly sensitive and specific indicator of catheter-related bacteraemia ⁸⁵⁾.

All cases of catheter-related infection in the setting of febrile neutropenia require decision-making on the choice and duration of i.v. antibiotics, and the need for catheter removal. When catheter-related infection is suspected, and the patient is stable, the catheter should not be removed without microbiological evidence of infection ⁸⁶⁾.

A glycopeptide such as vancomycin should be administered through the line when possible to cover Gram-positive organisms. Teicoplanin is a useful alternative as it can be administered once daily as a line lock. Success in treating catheter-related infection without removing the catheter depends on the pathogen isolated in the blood cultures.

In catheter-related infection due to coagulase-negative Staphylococcus, an attempt at preserving the catheter can be made if the patient is stable. Catheter retention does not have an impact on the resolution of coagulase-negative Staphylococcus bacteraemia but is a significant risk factor for recurrence in those patients in whom the catheter was retained.

Removal of the line is indicated in the context of tunnel infections, pocket infections (implanted port system), persistent bacteraemia despite adequate treatment, atypical mycobacterial infection and candidaemia. With regard to line infections caused by Staphylococcus aureus, the literature is divided. The desire to preserve the line must be balanced against the risk of metastatic spread by bloodstream seeding. The recommendation should be to remove the line if at all possible, while recognising that, with careful management, it might be possible to maintain it for a short period. Persistent fever and bacteremia despite appropriate antibiotics are indications for line removal.

Pneumonia

If pneumonia in an outpatient is diagnosed either on clinical grounds and/or on the basis of radiological imaging, antibiotic cover may be extended to treat atypical organisms such as Legionella and Mycoplasma by adding a macrolide or a fluoroquinolone antibiotic to a β-lactam antibiotic. Consideration for infection with Pneumocystis jirovecii should be given in patients who present with high respiratory rates and/or desaturate readily off oxygen or on minimal exertion. Predisposing factors include prior corticosteroid therapy, use of immune suppressants after organ transplantation and exposure to purine analogues, as well as lack of reliable chemoprophylaxis with co-trimoxazole ⁸⁷⁾. In high-risk patients with profound prolonged neutropaenia and lung infiltrates, early treatment with a mould-active antifungal agent is recommended.

Lung infiltrates

Patients with AML during remission induction ChT and those undergoing allogeneic haematopoietic stem cell transplantation with prior conditioning cancer chemotherapy are at risk of invasive fungal infections (namely aspergillosis) due to prolonged and profound neutropaenia ⁸⁸⁾. Frequent assessment of initial response to antibacterial therapy is essential, and, in the absence of prompt improvement, further investigations are warranted. If invasive aspergillus is suspected, a high-resolution chest computed tomography (CT) scan should be carried out on the same day, looking for typical features such as nodules with halos or ground-glass change, and galactomannan should be measured in serum. If any infiltrate is found, bronchoalveolar lavage should be undertaken if possible.

Advice from an infectious diseases specialist or clinical microbiologist is recommended, and an appropriate therapy against infection with fungi or Pneumocystis species should be instituted. The choice of antifungal agents will depend on centres, individual patients and use of prior prophylactic therapy ⁸⁹⁾.

Therapy for presumed aspergillosis (for cases with typical infiltrates on CT) could consist of either voriconazole or liposomal amphotericin B ⁹⁰⁾. These antifungals can be combined with an echinocandin in unresponsive disease. A precise microbiological diagnosis is highly desirable in patients suspected of invasive fungal infection, as the sensitivity to various antifungal agents is variable among different species.

High-dose co-trimoxazole is the treatment of choice for suspected Pneumocystis infection.

Vesicular lesions/suspected viral infection

After appropriate samples are taken, therapy with aciclovir should be initiated. Ganciclovir (or foscarnet) should be substituted only when there is a high suspicion of invasive cytomegalovirus infection ⁹¹⁾.

Suspected meningitis or encephalitis

Lumbar puncture (if in any way possible before the institution of antibiotics) is mandatory in these rare cases. Bacterial meningitis should be treated with ceftazidime plus ampicillin (to cover for Listeria monocytogenes) or meropenem. Viral encephalitis is treated with a high dose of aciclovir.

Cellulitis

The addition of vancomycin broadens the cover against skin pathogens. Linezolid and daptomycin are emerging alternatives to glycopeptides; however, more clinical experience is needed, especially in neutropaenic patients.

Intra-abdominal or pelvic sepsis

If clinical or microbiological evidence of intra-abdominal or pelvic sepsis exists, metronidazole should be commenced, unless the patient is on a carbapenem or piperacillin–tazobactam, which have adequate anaerobic coverage.

Diarrhea

Assessment for Clostridium difficile is needed and, if suspected, oral vancomycin or metronidazole treatment should be administered.

Candidiasis

Patients at risk of disseminated candidiasis are those with prolonged neutropaenia and especially those with haematological malignancies undergoing myeloablative therapy ⁹²⁾. Candidaemia can be diagnosed on blood culture; however, cultures may take several days to become positive. Empirical initiation of antifungal therapy is recommended in patients whose fever fails to respond to broad-spectrum antibiotics after 3–7 days of appropriate treatment. A CT scan of the liver and spleen should be carried out before commencing anti-Candida treatment, looking for typical changes.

First-line empirical treatment depends on what is known about the patient. Liposomal amphotericin B and an echinocandin antifungal such as caspofungin are appropriate first-line treatments if the patient has already been exposed to an azole or if the patient is known to be colonised with non-albicans Candida. Fluconazole can be given first line provided the patient is at low risk of invasive aspergillosis; local epidemiological data suggest low rates of azole-resistant isolates of Candida and the patient has not received an azole antifungal as prophylaxis. Once begun, antifungal treatment should be continued until neutropaenia has resolved, or for at least 14 days in patients with a demonstrated invasive Candida infection.

Specific needs for preventing other opportunistic infections are required in patients with haematological malignancies, namely those undergoing haematopoietic stem cell transplants ⁹³⁾.

Autoimmune neutropenia

Autoimmune neutropenia involves neutrophil-specific antibodies in the blood that actually attack the body’s own neutrophils. Severe acute neutropenia discovered in older children and adults unassociated with an acute viral syndrome may represent autoimmune neutropenia. However, demonstration of neutrophil antibodies is required to differentiate autoimmune neutropenia from benign chronic idiopathic neutropenia. Presence of neutrophil-specific antibodies can result in increased destruction of the body’s own blood neutrophils. Physical examination in these patients is usually unremarkable, but occasionally splenomegaly is noted. Marrow finding generally reflect that of “bone marrow arrest” – where adeuate numbers of early myeloid cells can be identified, but more mature myeloid elements appear lacking. The level of this “arrest” seems to vary between patients, and may reflect patient variability with regard to the myeloid antigen (early versus late) target by autoantibodies. Since young patients with autoimmune neutropenia are likely to have a relatively benign course, most do not appear to require treatment of any kind. In some children where severe infections occur, treatment with G-CSF is indicated. In most children the blood counts normalize during the first 2 – 3 years. In patients with recurrent infections, treatment with corticosteroids results in improved neutrophil counts in about half of patients. The majority of patients less than 2 years of age spontaneously achieve a durable remission within 3 years of their initial diagnosis. In contrast, adults and children over the age of 2 tend to have accompanying immunologic abnormalities and appear less likely to improve spontaneously over time. Similarly, older patients appear more resistant to therapeutic interventions including corticosteroids, intravenous immune globulin, and splenectomy. Two patients have acheived clinical improvement with cyclosporine.

Autoimmune neutropenia is occasionally seen in young people (20 – 40 year age group) predominantly women and in this setting is often associated with other disorders or conditions ⁹⁴⁾.

Congenital neutropenia

Congenital neutropenia or Kostmann’s syndrome, is a form of severe chronic neutropenia ⁹⁵⁾. Kostmann, a Swedish physician who described a large family with several severely affected members, originally described this disease entity in 1956. Inherited in both an autosomal dominant and recessive manner, this syndrome is most often recognized at birth or shortly thereafter because of significant fever and infection. Oomphalatis, cellulitis, and perirectal abscesses are particularly common. Morphologic examination of bone marrow from these patients usually reveals almost no evidence of developing neutrophils beyond the promyelocyte stage. However, formation of monocytes and eosinophils usually remains normal. In vitro cultures demonstrate adequate numbers of colony forming cells (CFCGM), in which normal maturation of progenitor cells into mature neutrophils variably occurs. Upon the exposure to supraphysiologic levels of recombinant human granulocyte colony stimulating factor (rHuGCSF), however, these CFC-GM often form mature neutrophils. While this observation might suggest impaired synthesis of G-CSF in these patients, biologically active levels of this cytokine are usually elevated or normal. Hence, the G-CSF receptor somehow fails to transduce its signal appropriately.

G-CSF receptors appear normal in number and binding affinity in almost all patients evaluated. However, occasional children with Kostmann’s syndrome – almost all in transition to acute myeloid leukemia (AML) – have been shown to manifest abnormalities of the receptor for G-CSF. In these rare cases, somatic mutation in one of the two alleles prevents function of the receptor encoded by the remaining normal allele. This mutated receptor appears to disrupt the normal regulation of myeloid growth, and might facilitate the evolution of leukemic subpopulations. It should be emphasized, however, that for the large majority of patients with Kostmann’s syndrome, no obvious defect has been detected – suggesting a postreceptor problem.

Cyclic neutropenia

Cyclic neutropenia is a rare disorder that causes frequent infections and other health problems in affected individuals ⁹⁶⁾. People with cyclic neutropenia have recurrent episodes of neutropenia during which there is a shortage (deficiency) of neutrophils. The episodes of neutropenia are apparent at birth or soon afterward. For most affected individuals, neutropenia recurs every 21 days and lasts about 3 to 5 days ⁹⁷⁾.

Cyclic neutropenia is a rare condition and is estimated to occur in 1 in 1 million individuals worldwide.

Cyclic neutropenia appears to affect males and females in equal numbers. Most cases of cyclic neutropenia are thought to be present at birth (congenital); however, in some cases, the symptoms may not become obvious until childhood, adolescence, or early adulthood.

Cyclic neutropenia is a subdivision of severe chronic neutropenia. Severe chronic neutropenia is estimated to affect approximately 0.5 to 1 per million population in the United States ⁹⁸⁾.

Neutropenia makes it more difficult for the body to fight off pathogens such as bacteria and viruses, so people with cyclic neutropenia typically develop recurrent infections of the sinuses, respiratory tract, and skin. Additionally, people with this condition often develop open sores (ulcers) in the mouth and colon, inflammation of the throat (pharyngitis) and gums (gingivitis), recurrent fever, or abdominal pain. People with cyclic neutropenia have these health problems only during episodes of neutropenia. At times when their neutrophil levels are normal, they are not at an increased risk of infection and inflammation.

Cyclic neutropenia causes

Cyclic neutropenia may be inherited or acquired. Some cases are present at birth (congenital) and appear to occur randomly for no apparent reason (sporadically). There have been reports in the medical literature in which individuals within several multigenerational families (kindreds) have an increased incidence of cyclic neutropenia. In such familial cases, the disorder may be inherited as an autosomal dominant trait.

Investigators have determined that cases of sporadic and autosomal dominant cyclic neutropenia may be caused by disruption or changes (mutations) of the ELANE gene located on the short arm (p) of chromosome 19 (19p13.3) ⁹⁹⁾.

Mutations in the ELANE gene cause cyclic neutropenia. The ELANE gene provides instructions for making a protein called neutrophil elastase, which is found in neutrophils. When the body starts an immune response to fight an infection, neutrophils release neutrophil elastase. This protein then modifies the function of certain cells and proteins to help fight the infection.

ELANE gene mutations that cause cyclic neutropenia lead to an abnormal neutrophil elastase protein that seems to retain some of its function. However, neutrophils that produce abnormal neutrophil elastase protein appear to have a shorter lifespan than normal neutrophils. The shorter neutrophil lifespan is thought to be responsible for the cyclic nature of this condition. When the affected neutrophils die early, there is a period in which there is a shortage of neutrophils because it takes time for the body to replenish its supply.

Cyclic neutropenia inheritance pattern

Cyclic neutropenia is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder.

In cases where the autosomal dominant condition does run in the family, the chance for an affected person to have a child with the same condition is 50% regardless of whether it is a boy or a girl. These possible outcomes occur randomly. The chance remains the same in every pregnancy and is the same for boys and girls.

• When one parent has the abnormal gene, they will pass on either their normal gene or their abnormal gene to their child. Each of their children therefore has a 50% (1 in 2) chance of inheriting the changed gene and being affected by the condition.
• There is also a 50% (1 in 2) chance that a child will inherit the normal copy of the gene. If this happens the child will not be affected by the disorder and cannot pass it on to any of his or her children.

In most cases, an affected person inherits the mutation from one affected parent. Other cases result from new mutations in the gene and occur in people with no history of the disorder in their family. This is called a de novo mutation.

Figure 9 illustrates autosomal dominant inheritance. The example below shows what happens when dad has the condition, but the chances of having a child with the condition would be the same if mom had the condition.

Figure 9. Cyclic neutropenia autosomal dominant inheritance pattern

Cyclic neutropenia symptoms

The primary finding associated with cyclic neutropenia is a severe chronic decrease in certain white blood cells (neutrophils). In most cases, episodes of neutropenia recur every 21 days (cyclic) and may last for three to six days. The cycling period usually remains constant and consistent among affected individuals. In addition, abnormal levels of red blood cells that assist in clotting (platelets), immature red blood cells (reticulocytes), and other types of white blood cells (monocytes) may occur. The monocyte count invariable increases during the periods of neutropenia.

During episodes of neutropenia, affected individuals may experience fever, a general feeling of ill health (malaise), inflammation and ulceration of the mucous membranes of the mouth (stomatitis), inflammation of the throat (pharyngitis), inflammation and degeneration of the tissues that surround and support the teeth (periodontal disease), and/or loss of appetite. Peridontal disease may result in loosening of teeth and early tooth loss in young children.

Individuals with cyclic neutropenia may be abnormally susceptible to various bacterial infections that often affect the skin, digestive (gastrointestinal) tract, and respiratory system. Such bacterial infections vary in severity and, in some cases, may result in life-threatening complications.

Cyclic neutropenia diagnosis

A diagnosis of cyclic neutropenia is made based upon a detailed patient history and thorough clinical evaluation. A diagnosis may be confirmed by monitoring an individual’s neutrophil count twice or three times per week for six weeks. Individuals with cyclic neutropenia should be genetically tested for mutations in the ELANE gene.

Cyclic neutropenia treatment

Prompt, appropriate treatment of the infections associated with cyclic neutropenia is important. Such treatment may include antibiotic therapy. Careful oral and dental care is also required. In addition, individuals with cyclic neutropenia should avoid activities that may cause minor injuries.

A synthetic drug that stimulates the bone marrow’s production of neutrophils (recombinant human granulocyte-colony stimulating factor [rhG-CSF]) has been used to treat severe chronic neutropenia. One form, the orphan drug neupogen (Filgrastim), has been approved by the Food and Drug Administration for use in the treatment of severe chronic neutropenia. Studies have shown that long-term therapy can elevate the numbers of neutrophils to normal range in most individuals, thereby reducing infections and other associated symptoms. Careful evaluation prior to initiation of such therapy and ongoing observation during therapy are essential to ensure the long-term safety and effectiveness of such treatment in individuals with severe chronic neutropenia. Neupogen is manufactured by Amgen Inc.

Genetic counseling may be of benefit for individuals with inherited forms of cyclic neutropenia and their families. Other treatment is symptomatic and supportive.

Refractory epilepsy

Intractable epilepsy also called “refractory epilepsy”, “uncontrolled epilepsy”, “difficult to control epilepsy” or “drug resistant epilepsy”, is hard to treat epilepsy that does not respond well to trials of at least two seizure medications ¹⁾. Some experts define a patient as having refractory seizures if treatment fails to achieve seizure freedom for 12 months or more, for whatever reason ²⁾. The generally accepted definition of refractory seizures was proposed by Berg: failure of two or more drugs and occurrence of one or more seizures per month over 18 months ³⁾.

The International League Against Epilepsy (https://www.ilae.org/files/dmfile/Epigraph-2016-2_Snead-9-MRE_Guidelines2016.pdf) has proposed the following definition of drug resistant epilepsy and suggests that this term be used instead of the term ‘refractory epilepsy’.

• Drug resistant epilepsy occurs when a person has failed to become (and stay) seizure free with adequate trials of two seizure medications called anti-epileptic drugs (AEDs).
• These seizure medications must have been chosen appropriately for the person’s seizure type, tolerated by the person, and tried alone or together with other seizure medications.

Studies suggest that epilepsy fails to come quickly under control with medicines in about one-third of cases, but the true frequency depends upon the definition of uncontrolled.

Most epilepsy specialists agree that refractory epilepsy is epilepsy for which seizures are frequent and severe enough, or the required therapy for them troublesome enough, to seriously interfere with quality of life ⁴⁾.

Half of the people with epilepsy are children and up to 30% become refractory to medications and develop intractable epilepsy ⁵⁾. Children with intractable epilepsy are exposed to many treatments and concomitant side effects ⁶⁾ and have suboptimal growth and diets compared to healthy children ⁷⁾.

However, in more recent years, the epilepsy community has recognized the need to continue striving for “no seizures” and the best control possible.

Seizures can be uncontrolled for four broad reasons.

1. The diagnosis is wrong.
2. The treatment is wrong.
3. Despite the best treatment, triggers or lifestyle factors may affect seizure control.
4. Properly diagnosed seizures do not respond to the best medical treatment.

Not all uncontrolled seizures are considered refractory or drug resistant. For example:

• If the diagnosis is corrected and seizures can be brought under control with a different treatment, then they would not be considered refractory.
• If triggers of lifestyle factors could be avoided or modified preventing breakthrough seizures, then medication therapy may work better. A person in this situation would not be considered drug resistant, but different drug trials may be considered and non-drug treatments may be considered to help control seizures.

Refractory epilepsy causes

Incorrect diagnosis

An incorrect diagnosis of epilepsy is more common than most people might think. One chart review study by Smith and colleagues in England found that 13% of patients referred for refractory epilepsy did not have epilepsy. If seizures are not controlled, then a reasonable first question is: “Are the episodes really seizures?” A number of conditions can imitate seizures. Some, but certainly not all, are listed here.

Imitators of epilepsy

• Fainting (syncope)
• Mini-strokes (transient ischemic attacks or TIAs)
• Hypoglycemia (low blood sugar)
• Migraine with confusion
• Sleep disorders, such as narcolepsy and others
• Movement disorders: tics, tremors, dystonia
• Fluctuating problems with body metabolism
• Panic attacks
• Nonepileptic (psychogenic) seizures

Experienced clinicians are skilled at using a combination of the medical history, the physical exam and certain laboratory tests to determine whether sudden episodes with alteration in sensation, strength, behavior or awareness are seizures or one of the imitators. But sometimes this is difficult. People have been referred to epilepsy centers for brain surgery, when their underlying condition was not epilepsy, but one of the imitators.

Poor or less than optimal seizures treatment

Another reason for uncontrolled seizures is poor or less than optimal treatment. In other words, the ‘wrong treatment’ is being used to treat the seizures. Common reasons for suboptimal treatment are listed below.

Reasons for suboptimal treatment of seizures:

• Using the wrong medication
• Inadequate doses of medicine
• Polypharmacy and toxicity
• Missing doses (poor compliance)
• Complicating factors (illness, sleep deprivations, extreme stress).

True intractable epilepsy or difficulty controlling seizures can result from not tolerating seizure medications or seizures not responding to the medicines.

All medications have potential side effects, but some people experience them more often than others, or the side effects are more bothersome. Sometimes people develop allergies to medicines or just can’t tolerate non- allergy side effects. People who are very sensitive to seizure medicines are less likely to find one that they can tolerate and that will work! Seizures that might be easy to treat with medicine become hard to treat when the best medicines are off-limits. Some people with multiple drug resistance have a type of metabolism that quickly inactivates or isolates drugs, causing them to be less effective. When this happens, exploring other treatments like surgery may be helpful.

Another common problem is reaching a “honeymoon” state or as it is officially known, developing medication “tolerance.” In this situation, a new drug works for a few months and then seizures return. The cycle repeats with each new medication. Such patients can end up on a stressful “rotation diet” of different medicines. It is another form of drug resistance.

When seizures persist after at least two good trials of the proper drugs at the right dose, a person would be considered to have intractable or drug resistant epilepsy.

Using the wrong medication

Many seizure medications have useful actions against a number of different seizure types. But some medicines are not right for certain types of seizures. Carbamazepine (Tegretol), for example is usually good for treating complex partial seizures, but not absence seizures. Ethosuximide (Zarontin) is good for absence, but not complex partial seizures. Since absence and complex partial seizures can occasionally be confused with each other, there is a chance for using the wrong medicine.

Inadequate or incorrect doses of medicine

People vary widely in their response to seizure medicines. Every medicine has a suggested dosage range, but that range is too high for some and too low for others. If a dose that is too high for an individual is used, a person will have too many side effects. A dose that is too low may lead to seizures.

• Some people with uncontrolled seizures may become seizure free when the medication daily dosages are increased.
• Others may do better on low doses of antiepileptic drugs (AEDs), which leads to less medication side effects.
• Measuring blood levels of antiepileptic drugs (AEDs) sometimes helps to guide therapy, but levels are not as important as carefully asking about side effects and seizure control. The newer seizure medicines often have fewer side effects than the older seizure medicines.

Polypharmacy and toxicity

Polypharmacy is the use of several medications at once to treat the same condition. Some people require more than one drug to control their epilepsy, but additional medications rarely lead to complete freedom from seizures.

Two important studies, one by Mattson and colleagues ⁸⁾ and the other by Kwan and Brodie ⁹⁾ suggest that if a person is not seizure-free on a good dosage of a single antiepileptic drug, then adding a second will make them seizure-free only about 10% of the time. The second drug may help, but not usually to the point of complete control. Two drugs have more side effects than does one drug, and three drugs more than two.

Patients taking polypharmacy may have so many side effects that it is often difficult for someone to tolerate a higher dose for any of their antiepileptic drugs.

Also, polypharmacy can lead to drug interactions that limit how well the drug may work or increases side effects of another drug.

One way to treat refractory seizures in people taking many medications is to streamline or simplify the medicines. Sometimes “less can be more,” especially if it lowers overall levels of side effects and allows an increase in the drug that is most effective. Making these changes can be hard, with a period of seizures and side effects during the changes, until the new and improved regimen is established.

Missing antiepileptic drug doses (poor adherence or compliance)

Missing medication is a cause of breakthrough seizures. Almost everyone forgets to take pills, especially if the pill schedule is complicated. In the medical field, this is called “poor compliance.” Learn about the importance of adherence and ways to make taking medications easier It can make a real difference!

Complicating factors (illness, sleep deprivations, extreme stress)

Complicating or precipitating factors for seizures can make them more difficult to control. These again vary with the individual. Triggers may include alcohol, exercise, flashing lights or certain patterns, general illness, heavy breathing (hyperventilation), lowering dose of medicines, taking certain medications, the menstrual cycle, missing medications, missing sleep, recreational drugs, and stress. All too often, a seizure breakthrough is preceded by one of these, or other personally relevant, factors.

Refractory epilepsy diagnosis

Diagnosing epilepsy is not simple. Doctors gather lots of different information to assess the causes of seizures. If you have had two or more seizures that started in the brain you may be diagnosed with epilepsy. Getting a diagnosis is not always easy as there is no single test that can diagnose epilepsy. If there is a possibility that you have epilepsy, the National Institute for Health and Care Excellence recommends that you are referred to an epileptologist (a doctor who is trained in diagnosing and treating epilepsy) within two weeks.

Your diagnosis is based on finding out what happened to you before, during and after your seizures. For example, some types of faints can look like epileptic seizures, and often before fainting a person feels cold, clammy and their vision goes blurry. But epileptic seizures happen very suddenly and a person may have no warning that a seizure is about to happen.

A number of tests are used to determine whether a person has a form of epilepsy and, if so, what kind of seizures the person has.

Medical history

Taking a detailed medical history, including symptoms and duration of the seizures, is still one of the best methods available to determine what kind of seizures a person has had and to determine any form of epilepsy. The medical history should include details about any past illnesses or other symptoms a person may have had, as well as any family history of seizures. Since people who have suffered a seizure often do not remember what happened, caregiver or other accounts of seizures are vital to this evaluation. The person who experienced the seizure is asked about any warning experiences. The observers will be asked to provide a detailed description of events in the timeline they occurred.

Blood tests

Blood samples may be taken to screen for metabolic or genetic disorders that may be associated with the seizures. They also may be used to check for underlying health conditions such as infections, lead poisoning, anemia, and diabetes that may be causing or triggering the seizures. In the emergency department it is standard procedure to screen for exposure to recreational drugs in anyone with a first seizure.

Imaging and monitoring

An electroencephalogram, or EEG, can assess whether there are any detectable abnormalities in the person’s brain waves and may help to determine if antiseizure drugs would be of benefit. This most common diagnostic test for epilepsy records electrical activity detected by electrodes placed on the scalp. Some people who are diagnosed with a specific syndrome may have abnormalities in brain activity, even when they are not experiencing a seizure. However, some people continue to show normal electrical activity patterns even after they have experienced a seizure. These occur if the abnormal activity is generated deep in the brain where the EEG is unable to detect it. Many people who do not have epilepsy also show some unusual brain activity on an EEG. Whenever possible, an EEG should be performed within 24 hours of an individual’s first seizure. Ideally, EEGs should be performed while the person is drowsy as well as when he or she is awake because brain activity during sleep and drowsiness is often more revealing of activity resembling epilepsy. Video monitoring may be used in conjunction with EEG to determine the nature of a person’s seizures and to rule out other disorders such as psychogenic non-epileptic seizures, cardiac arrhythmia, or narcolepsy that may look like epilepsy.

A magnetoencephalogram (MEG) detects the magnetic signals generated by neurons to help detect surface abnormalities in brain activity. MEG can be used in planning a surgical strategy to remove focal areas involved in seizures while minimizing interference with brain function.

The most commonly used brain scans include CT (computed tomography), PET (positron emission tomography) and MRI (magnetic resonance imaging). CT and MRI scans reveal structural abnormalities of the brain such as tumors and cysts, which may cause seizures. A type of MRI called functional MRI (fMRI) can be used to localize normal brain activity and detect abnormalities in functioning. SPECT (single photon emission computed tomography) is sometimes used to locate seizure foci in the brain. A modification of SPECT, called ictal SPECT, can be very helpful in localizing the brain area generating seizures. In a person admitted to the hospital for epilepsy monitoring, the SPECT blood flow tracer is injected within 30 seconds of a seizure, then the images of brain blood flow at the time of the seizure are compared with blood flow images taken in between seizures. The seizure onset area shows a high blood flow region on the scan. PET scans can be used to identify brain regions with lower than normal metabolism, a feature of the epileptic focus after the seizure has stopped.

Developmental, neurological, and behavioral tests

Tests devised to measure motor abilities, behavior, and intellectual ability are often used as a way to determine how epilepsy is affecting an individual. These tests also can provide clues about what kind of epilepsy the person has.

Refractory epilepsy treatment

When seizures are not controlled, despite best efforts, different therapies are available to people with epilepsy and their health care team.

• Talk to your doctor to reevaluate the diagnosis and medication therapy.
• Make sure you are doing everything you can to take the medicines consistently and manage or avoid seizure triggers.
• Consider a referral to an epilepsy specialist called an epileptologist and specialized epilepsy center. An Epilepsy Center takes a comprehensive approach to medical, psychological, and social problems associated with seizures. They should be capable of providing the full range of treatments for epilepsy, both medication and non-drug therapies.
• Find an American Epilepsy Society Doctor (https://my.aesnet.org/FindaDoctor)
• Find an Epilepsy center (https://www.naec-epilepsy.org/about-epilepsy-centers/find-an-epilepsy-center)
• Learn about non-drug therapies for epilepsy
  • Epilepsy surgery
  • Neurostimulation devices
  • Dietary therapy
  • Experimental trials

Antiepileptic drug therapy

There are at least 21 antiepileptic drugs available today, 15 of which have been recently released. Given that there are few robust randomized controlled trials or comparative studies, determining which antiepileptic drug to use can be challenging. The following general principles can be applied. If the trial of two antiepileptic drugs is found to be ineffective by a neurologist, patients should be referred to an epileptologist as per the Provincial Guidelines for the Management of Epilepsy in Adults and Children ¹⁰⁾.

Practice recommendations for antiepileptic drug trial:

1. Optimize the dose of each antiepileptic drug by increasing the dose incrementally. If the maximum dose is ineffective, introduce a second antiepileptic drug while continuing on the first. If seizure control is achieved, consider tapering the first antiepileptic drug. The advice to “start low and go slow” is appropriate ¹¹⁾.
2. If one or two antiepileptic drugs are ineffective, rational polytherapy should be explored. There is little systematic study of rational polytherapy. Considerations include a higher incidence of side effects when multiple antiepileptic drugs are used.
3. Consider using antiepileptic drugs with different mechanisms of action. However, although mechanisms of action have been described for a number of antiepileptic drugs, it is not certain that these are their only mechanisms of action or even the most important. For example, Levetiracetam affects the SV2a receptor on the synaptic vesicle but also has calcium channel modulating effects and GABAergic properties.
4. Avoid using an antiepileptic drug that may worsen or provoke seizures. Carbamazepine, Oxcarbazepine, Phenytoin, Vigabatrin and Tiagabine may worsen myoclonus and absence seizures. Gabapentin and Lamotrigine may worsen myoclonus ¹²⁾. Benzodiazepines given intravenously may worsen tonic seizures but may be very useful in treating Lennox-Gastaut and does not contraindicate their use ¹³⁾.

Recent literature has concentrated on the most recently introduced antiepileptic drugs. There have been few class 1 studies and no comparative studies done on these new antiepileptic drugs ¹⁴⁾. The most recently available antiepileptic drugs are Rufinamide, Lacosamide, Perampanel, Eslicarbazepine and Retigabine (ezogabine). As per literature its use is limited because of the long term effect of developing a blue hue to the skin and retina ¹⁵⁾.

Despite the agreed need for consideration of many factors in deciding which antiepileptic drug to use, the most important consideration is still the type of seizure. Greater precision can be applied when a particular epilepsy syndrome is identified (e.g. childhood absence epilepsy, juvenile myoclonic epilepsy) but many patients do not have an easily identifiable syndrome. Using a broad-spectrum anticonvulsant may be an efficient approach for the large number of children who do not have a defined epilepsy syndrome. These broad spectrum anticonvulsants are:

• Valproate
• Levetiracetam
• Lamotrigine
• Topiramate
• Clobazam

Clobazam is safe and effective for seizures associated with Lennox-Gastaut syndrome ¹⁶⁾, focal epilepsy in tuberous sclerosis complex and other refractory epilepsies in childhood. There is no data to recommend one of these antiepileptic drugs over another and the age of patient, concomitant medications, potential side effects, ease of use and cost to the patient are important considerations when data on efficacy and effectiveness are lacking.

Ideal antiepileptic drug polytherapy would combine supra-additive (synergistic) efficacy with infra-additive toxicity. The following list of anticonvulsants classified by mechanism of action is intended to encourage the use of antiepileptic drugs with different mechanisms of action rather than combining antiepileptic drugs with the same mechanism of action.

Limited data has suggested the following combinations ¹⁷⁾.

• Ethosuximide-Valproate
• Lacosamide-Levetiracetam
• Stiripentol-Clobazam
• Lamotrigine-Valproate

NOTE: This combination has the best human evidence for synergy especially for focal seizures. The question whether the addition of valproate causes apparent synergy by inhibiting lamotrigine metabolism and increasing lamotrigine levels has been studied and the limited data does not show this. Nonetheless, because of the recognised effect of valproate on lamotrigine, the latter drug should be introduced very cautiously in patients on valproate. Current practice would be to use doses of lamotrigine that are 25% of usual introductory doses and in children a maximum dose of 5 mg/kg/day is suggested. However, the introduction of valproate in someone who is already on lamotrigine is said not to cause any risk for sensitivity reactions such as Stevens-Johnson syndrome or toxic epidermal necrolysis.

For the common medical refractory childhood epilepsy syndromes the following suggestions are made ¹⁸⁾:

• Infantile spasms: ACTH, high dose prednisone/prednisolone, vigabatrin,
• Lennox-Gastaut Syndrome: Lamotrigine, topiramate. Lamotrigine can exacerbate myoclonic seizures in select patients. Lamotrigine and topiramate appear to have a synergistic effect. Rufinamide and clobazam also have demonstrated effect.
• Severe Myoclonic Epilepsy of Infancy (Dravet syndrome): Because this is a SCN1A-based voltage gated sodium channel disorder, antiepileptic drugs targeting this should not be used. Recommended treatments are valproate, clonazepam and clobazam. The addition of stiripentol to valproate and clobazam has been shown to be effective
• Landau-Kleffner Syndrome or Electrical Status Epilepticus in Sleep: High dose roal diazepam at night, valproate, levetiracetam. If antiepileptic drugs are ineffective, immunomodulatory treatments should be considered including steroids and intravenous immune globulin alone (IVIg).

Vagus nerve stimulation

Vagus nerve stimulation therapy, or vagus nerve stimulation, is a way of controlling seizures in people who do not respond to medications and may not respond to surgery. The vagus nerve sends information from your neck down to the chest and stomach, and then back up again. The vagus nerve then sends information up to the brain. Stimulation of the vagus nerve can change the likelihood of the brain to have seizures.

Vagus nerve stimulation therapy consists of a device placed under the skin in the left side of the chest. An electrode attached to the generator is then placed under the skin and connects with the vagus nerve in the left side of the neck.

Preprogrammed stimulation can be delivered from the generator in the chest to the vagus nerve. Settings can be adjusted by a nurse and doctor trained in the use of vagus nerve stimulation therapy.

The stimulation doesn’t work right away, but after a few months of therapy, about 25 to 30% of people may see that seizures decrease by 50% or more. Usually seizure control improves over time, with up to about 45% of people having seizures decrease at least by 50% after 1 to 2 years of therapy.

• Complete seizure freedom by vagus nerve stimulation happens in only small numbers of people. And in some people, it doesn’t work at all.
• Vagus nerve stimulation is not considered a substitute for seizure medications. People continue to take seizure medications while using vagus nerve stimulation. However, if the vagus nerve stimulation works, some people can lower the number or dose of medications and lessen side effects.
• Side effects of vagus nerve stimulation are usually mild, including hoarseness and coughing, mostly while becoming use to the stimulation.
• Vagus nerve stimulation is also approved by the U.S. Food and Drug Administration (FDA) for depression that does not respond to other treatments.

Dietary therapies

When medicines don’t work, dietary therapies have been found to help in a number of people. Like surgery or vagus nerve stimulation, it doesn’t work in everyone. It has been used most often in children, as it’s easier to control what young children eat. However, some of the diets have also been used in adults and showed very promising results. The diets used most often include:

• Ketogenic Diet
• Modified Atkins Diet
• Low Glycemic Index Treatment

Ketogenic diet

The “classic” ketogenic diet is a special high-fat, low-carbohydrate diet that helps to control seizures in some people with epilepsy. The name ketogenic means that it produces ketones in the body (keto = ketone; genic = producing). Ketogenic diet is prescribed by a physician and carefully monitored by a dietitian. It is usually used in children with seizures that do not respond to medications. It is stricter than the modified Atkins diet, requiring careful measurements of calories, fluids, and proteins. Foods are weighed and measured.

Ketones are formed when the body uses fat for its source of energy. Usually the body uses carbohydrates (such as sugar, bread, pasta) for its fuel. Because the ketogenic diet is very low in carbohydrates, fats become the primary fuel instead. The body can work very well on ketones (and fats).

Ketones are not dangerous. They can be detected in the urine, blood, and breath. Ketones are one of the more likely mechanisms of action of the diet, with higher ketone levels often leading to improved seizure control. However, there are many other theories for why the diet will work.

The ketogenic diet is a treatment for intractable epilepsy and typically a third of the patients will experience a greater than 90% reduction in seizure frequency ¹⁹⁾. The ketogenic diet is often discontinued after three years, but in children whose seizures return during a gradual taper, the ketogenic diet can be extended for more than 10 years ²⁰⁾. Ketogenic diet treatment can result in height velocity deceleration and growth failure ²¹⁾.

Children who are on the ketogenic diet continue to take seizure medicines. Some are able to take smaller doses or fewer medicines than before they started the diet. This is usually attempted after 1 month on the diet. If the person goes off the ketogenic diet for even one meal, it may lose its good effect. So it is very important to stick with the ketogenic diet as prescribed. Being on a ketogenic diet allows for a sense of control over seizures by a parent (or person living with epilepsy). Many families comment on this and the how their ability to cook helps their child. Most major pediatric hospitals (and countries) have ketogenic diet centers – just ask.

Are any other medicine changes needed?

Because the ketogenic diet does not provide all the vitamins and minerals found in a balanced diet, the dietician will recommend vitamin and mineral supplements. The most important of these are calcium and vitamin D (to prevent thinning of the bones), B Vitamins, and selenium.

There are no anticonvulsants (seizure medicines) that should be stopped while on the ketogenic diet. Topiramate (Topamax) and zonisamide (Zonegran) do not have a higher risk of kidney stones while on the diet, but zonisamide can increase the chance of stones.

Medication levels do not likely change while on the ketogenic diet according to recent studies. All medications should be in as carbohydrate/sugar-free a form as possible to avoid hidden sugars. Most liquids are changed by pharmacists to pills.

Who will ketogenic diet help?

• Doctors usually recommend the ketogenic diet for children whose seizures have not responded to several different seizure medicines.
• The classic ketogenic diet diet is usually not recommended for adults, mostly because the restricted food choices make it hard to follow. However, the modified Atkins diet does work well. This also should be done with a good team of adult neurologists and dietitians.
• The ketogenic diet has been shown in many studies to be particularly helpful for some epilepsy conditions. These include infantile spasms, Rett syndrome, tuberous sclerosis complex, Dravet syndrome, Doose syndrome, and GLUT-1 deficiency. Using a formula-only ketogenic diet for infants and gastrostomy-tube fed children may lead to better compliance and possibly even improved efficacy.
• Recent studies have also shown that infants can be successfully started on dietary therapy too (https://www.epilepsy.com/article/2017/1/ketogenic-diet-neonates).
• Learn about Ketogenic Guidelines for Infants (https://www.epilepsy.com/article/2016/8/ketogenic-diet-guidelines-infants).
• The ketogenic diet works well for children with focal seizures, but may be less likely to lead to an immediate seizure-free result.
• In general, the ketogenic diet can always be considered as long as there are no clear metabolic or mitochondrial reasons not to use it.
• The ketogenic diet is sometimes started to help reduce or even stop anti-seizure drugs. However, that does not always occur – often it is a “partnership” between drugs and food to help reduce seizures that works.

What is it like to be on the ketogenic diet?

The typical “classical” ketogenic diet, called the “long-chain triglyceride diet,” provides 3 to 4 grams of fat for every 1 gram of carbohydrate and protein. That is about 90% of calories from fat.

Usually when the classic ketogenic diet is prescribed, the total calories are matched to the number of calories the person needs. For example, if a child is eating a 1500 calorie regular diet, it would be changed to a 1500 calorie ketogenic diet. For very young children only, the diet may be prescribed based on weight, for example 75 to 100 calories for each kilogram (2.2 pounds) of body weight. If it sounds complicated, it is. That’s why people need a dietician’s help when using ketogenic diet.

A ketogenic diet “ratio” is the ratio of fat to carbohydrate and protein grams combined.

• A 4:1 ratio is more strict than a 3:1 ratio and is typically used for most children.
• A 3:1 ratio is typically used for infants, adolescents, and children who require higher amounts of protein or carbohydrate for some other reason.

The kinds of foods that provide fat for the ketogenic diet are butter, heavy whipping cream, mayonnaise, and oils (e.g., canola or olive). Because the amount of carbohydrate and protein in the diet have to be restricted, it is very important to prepare meals carefully. No other sources of carbohydrates can be eaten.

The ketogenic diet is supervised by:

• a dietician who monitors the child’s nutrition and can teach parents and the child what can and cannot be eaten
• a neurologist who monitors medications and overall benefits

What happens first?

Typically the ketogenic diet is started in the hospital. The child traditionally begins by fasting (except for water) under close medical supervision for 18-24 hours. The ketogenic diet is then started, either by slowly increasing the calories or the ratio.

There is growing evidence that fasting is probably not necessary for long-term efficacy, although it does lead to a quicker onset of ketosis. Most centers today do NOT start with a fasting period. The primary reason for admission in most centers is to monitor for any increase in seizures on the diet, ensure all medications are carbohydrate-free, and educate the families.

Does ketogenic diet work?

Several studies ²²⁾, ²³⁾ have shown that the ketogenic diet does reduce or prevent seizures in many children whose seizures could not be controlled by medications.

• Over half of children who go on the diet have at least a 50% reduction in the number of their seizures.
• Some children, usually 10-15%, even become seizure-free.

Ketogenic diet side effects

• A person starting the ketogenic diet may feel sluggish for a few days after the diet is started. This can worsen if a child is sick at the same time as the diet is started.
• Make sure to encourage carbohydrate-free fluids during illnesses.
• Other side effects that might occur if the person stays on the diet for a long time are:
  • Kidney stones
  • High cholesterol levels in the blood
  • Constipation
  • Slowed growth
  • Bone fractures

How is the patient monitored over time?

• Early on, the doctor will usually see the child every 1 to 3 months.
• Blood and urine tests are performed to make sure there are no medical problems.
• The height and weight are measured to see if growth has slowed down.

Can the ketogenic diet ever be stopped?

If seizures have been well controlled for some time, usually 2 years, the doctor might suggest going off the ketogenic diet.

• Usually, the person is gradually taken off the ketogenic diet over several months or even longer. Seizures may worsen if the ketogenic diet is stopped all at once.
• Children usually continue to take seizure medicines after they go off the ketogenic diet.
• In many situations, the ketogenic diet has led to significant, but not total, seizure control. Families may choose to remain on the ketogenic diet for many years in these situations.

Responsive neurostimulation

At least 30% of people do not respond to seizure medicines. Some people can have surgery to remove where seizures start in the brain. This treatment is the only way to cure epilepsy, but it doesn’t work in everyone. On average, only about 60% of people can be free of disabling seizures from removal of a seizure focus in the temporal lobe. Vagus nerve stimulation therapy or dietary therapies, such as the ketogenic diet, may help many people. Another option is responsive neurostimulation. Responsive Neurostimulation is also known as as RNS® Therapy, is a new seizure treatment was approved by the U.S. Food and Drug Administration (FDA) in 2013.

The RNS® System is similar to a heart pacemaker. It can monitor brain waves, then respond to activity that is different from usual or that looks like a seizure. People cannot feel the stimulation once it’s programmed. It doesn’t cause pain or any unusual feelings. Responsive Neurostimulation Therapy has shown to reduce seizures and improve quality of life in most people who have used it.

Everyone’s seizures are a bit different, either in type, number, or pattern. Therefore an ideal way to treat seizures is personalizing the treatment to each person. The ability to give the treatment only when it’s needed (at the time of a seizure or suspected seizure activity in the brain) is a key feature of the RNS® System.

The Responsive Neurostimulation System is designed to work in 3 key ways:

1. Monitor brain waves at the seizure focus, all the time – even during sleep.
2. Detect unusual electrical activity that can lead to a seizure.
3. Respond quickly (within milliseconds) to seizure activity by giving small bursts or pulses of stimulation. This goal is to help brainwaves return to normal, even before it could turn into a seizure.

Most comprehensive epilepsy centers that provide epilepsy surgery can also offer the Responsive Neurostimulation System. Before having the RNS placed, a person must go though detailed testing to see where their seizures arise in the brain.

• The RNS® System is similar to a heart pacemaker. It can monitor brain waves, then respond to activity that is different from usual or that looks like a seizure.
• A device or stimulator is placed in the bone covering the brain. Tiny wires or leads are placed in one or two places on top of the brain where seizure activity may begin. These wires connect to the stimulator. Once the wires and device are placed, nothing can be seen.
• The system can give small pulses or bursts of stimulation to the brain when anything unusual is detected. This can stop seizure activity before the actual seizure begins. Or it could stop seizure activity from spreading from a small focal seizure to a generalized seizure.
• People cannot feel the stimulation once it’s programmed. It doesn’t cause pain or any unusual feelings.
• It’s not permanent. It can be turned off or removed if it doesn’t work or a person doesn’t wish to use it any longer.

Who can use the Responsive Neurostimulation System?

• The RNS® System has been approved by the FDA to treat focal or partial seizures in adults, 18 years and older.
• It’s used in addition to seizure medictions. This is called adjunctive or add-on treatment.
• It’s designed for people with refractory seizures. This means that a person continues to have seizures despite at least trials with two seizure medications.
• It’s used in people who can not have epilepsy surgery to remove where the seizures start or resective surgery has not worked.

How does the Responsive Neurostimulation System work?

A device like the Responsive Neurostimulation system changes or modulates brain activity to stop or prevent seizures.

The exact way that the Responsive Neurostimulation System works is not known. It is thought to act on a certain substance in the brain called an inhibitory neurostramitter. This type of substance acts to inhibit or stop activity from brain cells that could lead to seizures. This may explain how the RNS works in the short term. Yet it’s long-term effect may be caused by something else affecting how brain cells work more broadly.

How helpful is Responsive Neurostimulation Therapy?

Although the Responsive Neurostimulation System is not a cure for epilepsy, it has shown to reduce seizures in most people who have used it. So far, these effects appear to improve over time in many people.

Seizure Reducton Results

• 230 patients with the RNS® System were followed over time in a controlled trial ²⁴⁾. The average decrease in seizures was 44% after 1 year, 53% at 2 years, and up to 66% after 3 to 6 years of using Responsive Neurostimulation.
• The same trend was seen when some of these people were followed for 7 years. Seizures decreased by an average of 72%.
• So far, 2 out of 3 people with the Responsive Neurostimulation System (66%) had their seizures cut in half after 7 years of using it.
• Some people had extended times of being seizure free as well. In the open label study or long-term study, 1 out of 3 people reported periods of no seizures for 6 months in a row.

Quality of Life Results

Benefits of any therapy must also look at how a person feels and their quality of life. A study of 191 people ²⁵⁾ with the Responsive Neurostimulation System found improvements in quality of life aside from seizure control. These benefits did not appear due to changes in seizures or medicines. These included:

• Physical health
• Cogntitive functioning (for example thinking, remembering, and concentrating)
• Emotional health or mood
• Less worry about seizures
• Overall quality of life

Epilepsy surgery

• Surgery is a treatment option that offers some people a real solution to stopping their seizures.
• Surgery works best for people who have seizures that always begin in one area of the brain.
• There are many different types of epilepsy surgery. The type of surgery recommended will depend on many factors. The key factors are the type of seizures and where they start in the brain.
• Surgery typically involves opening the skull and removing the area of the brain where seizures start. There are less invasive options available too.
• Ask your health care team whether epilepsy surgery is an option for you.

Epilepsy surgery is a treatment used to help control seizures when seizures are not controlled by medications.

Epilepsy surgery is “neurosurgery,” which means it is surgery involving the brain. Doctors who do epilepsy surgery are neurosurgeons. Neurosurgeons who specialize in the care of people with seizures are found at comprehensive epilepsy centers.

Epilepsy centers are typically multi-disciplinary, meaning they have a coordinated team of experts in adult and pediatric epilepsy care, including:

• Epileptologists (neurologists who specialize in epilepsy)
• Nurses
• Psychologists
• Neurosurgeons who specialize in epilepsy
• Neuroradiologists who specialize in brain imaging

With more than one epileptologist on staff, there is a team of experts available to discuss challenging cases. The availability of broad expertise and input from colleagues in the same specialty is not available in a single-epileptologist clinic.

A comprehensive epilepsy center:

• Permits experts in multiple areas or disciplines to engage the person living with epilepsy and their caregivers
• Maximizes interaction between colleagues with an interest in epilepsy
• Facilitates coordination of care of people living with epilepsy and their families

Epilepsy surgery key points:

• Epilepsy surgery works best for people who have seizures that always begin in one area of the brain.
• Tests are done before surgery. This testing helps to find the area in the brain where seizures start. The tests also help to make sure the area where seizures begin is not involved in important brain functions that include speech, movement, or memory.
• Epilepsy surgery can reduce the number and severity of seizures a person has when compared to only taking medications.
• By removing the seizure focus in the brain, epilepsy surgery can, in most cases, successfully and safely stop seizures. Some people may need a second surgery to become seizure free. Although many people are permanently seizure free after surgery, seizures can come back in some people.

What actually happens during epilepsy surgery?

Currently, most cases of epilepsy surgery involve removing the area where seizures start. Typically, this involves creating an opening in the skull (the bone covering the brain) in a procedure called a craniotomy.

• Epilepsy surgery usually takes several hours.
• The person’s hair may be clipped short or the head shaved in the area where surgery will be done. This lessens the risk of infection.
• Anesthesia is given so the person is asleep and not aware during the surgery.
• Just like any surgery, heart rate, blood pressure, and oxygen levels are checked closely.
• A small part of the skull is opened so the surgeon can see the area of abnormal tissue to be removed.
• EEG (electroencephalogram) monitoring may be done during the surgery. This will confirm exactly where in the brain the seizures start and what area needs to be removed.
• In some cases, the person is woken up during the surgery so he or she can talk and respond to questions. This helps the surgeon test which areas of the brain control speech or movement. This is important to lessen the risks of these areas being affected during surgery. This part of the surgery is called “brain mapping.”
• Once the brain areas are mapped, the anesthesiologist will return the person to sleep with medication, and the neurosurgeon can safely remove the abnormal brain tissue causing the seizures.
• The piece of bone that was removed from the skull at the beginning of the surgery will then be secured back in its normal position. The skin overlying the skull is then closed, and a head bandage is applied.

What happens after epilepsy surgery?

Right after surgery, the person will be in a special recovery unit where the doctors and nurses will monitor you very closely as you wake up from anesthesia. Depending on the hospital, a person may spend the first night after surgery in the intensive care unit for close monitoring or may go directly to the neurosurgery or epilepsy unit.

In the first week after surgery:

• Some swelling of the scalp and face is usually seen. This is normal as the tissue will need some time to heal from the surgery.
• Headaches are also common.
• Medicines to treat these symptoms will be given.
• For most people, the swelling and head pain after surgery goes away within a few weeks.

Typically, people spend 3 to 4 days in the hospital after surgery. In some cases, a longer stay in the hospital is needed.

Usually, people can go home to recover. If a person needs more help or lives alone, they may go to a rehabilitation facility for a short time until they are ready to go home.

A person recovering from surgery needs to rest and slowly return to their normal daily routines:

• Activity is gradually increased.
• Most people are back to their usual activities in 4 to 6 weeks.
• There may be some restrictions or precautions depending on each person’s situation.

Seizure medicines are continued after surgery. Medicine helps to protect the brain during the healing and increases the person’s chances of being seizure free later on.

• If a person is seizure free after a year or more, medicines may be gradually lowered or tapered off.
• Changing medicines slowly may help the person’s chances of staying seizure free.

Each person should talk with their epilepsy team about what is best in their situation.

There are other steps to consider in recovering from brain surgery.

• One of the goals of epilepsy surgery is to improve a person’s quality of life. This may include support from a therapist, vocational counselor, social worker, physical or occupational therapist, or neuropsychologist.
• Finding support as you adjust to changes after surgery is an important part of your recovery.
• Remember, your epilepsy team will be there to support you through all stages leading up to surgery, during surgery, and recovery.

Immunotherapy

The main treatment options other than antiepileptic drugs include medications used when the immune system is involved. Evidence that the immune system is involved in the pathogenesis of epilepsy particularly, medically refractory epilepsy, has given rise to the use of adjunctive immunotherapy to slow or change the epileptogenic process. Medications include immunoglobulins, corticosteroids, plamapharesis and monocloncal antibodies such as rituximab, natalizumab. There is limited data of these treatments outside of specific epileptic encephalopathies such as West syndrome, Rasmussen encephalitis, Landau Kleffner and specific anitbody mediated encephalitis such as anti NMDA encephalitis.

Corticosteroids form one of the main treatment options. Corticosteroids cause immunosuppression by decreasing the function and numbers of lymphocytes, including both B cells and T cells. By inhibiting a critical transcription factor involved in the synthesis of many mediators (i.e., cytokines) and proteins (i.e., adhesion proteins) that promote an immune response, they blunt the capacity of the immune system to mount a response.

Corticosteroids have an anti-inflammatory effect by preventing the formation of prostaglandins and leukotrienes, two main factors in inflammation. This is mediated by the release of lipocortin which by inhibition of phospholipase A2 reduces arachidonic acid release.

Corticosteroids have been used as therapy in many epileptic syndromes including infantile spasms, an age specific epilepsy syndrome associated with epileptic spasms, and in many cases with neurodevelopmental regression and an EEG finding of hypsarrhythmia (West Syndrome).

Low dose ACTH, or vigabatrin should be considered for the treatment of infantile spasms. However hormonal therapy with prednisolone or other steroids have also been used but the review by Go et al. ²⁶⁾ found there was little evidence to suggest that prednisolone, dexamethasone, and methylprednisolone are as effective as ACTH for short-term treatment of infantile spasms.

Steroids are also used in Rasmussen’s Encephalitis which is a rare, sporadic but potentially severe immune-mediated brain disorder leading to unilateral hemispheric atrophy, associated progressive neurological dysfunction and poorly controlled seizures.

Prednisolone or prednisone started at a high dose and then slowly tapered down has been reported to have beneficial effects on seizures and neurological functions in several series, particularly
when started early on in the course ²⁷⁾. For long term steroid therapy, it has been recommended to start with boluses of intravenous methylprednisolone [e.g. 400 mg/m2/day ²⁸⁾ or, in children, 20 mg/kg/day ²⁹⁾ and then to introduce 1–2 mg/kg/day oral prednisolone or prednisone ³⁰⁾. This dose should be slowly reduced, ideally to a dose below the threshold of Cushing’s syndrome.

Bahi-Buisson et al. ³¹⁾ confirmed steroid treatment can be useful when given early on in the course of Rasmussen encephalitis, but they found that long term relapse can occur among the good responders requiring delayed hemispheric disconnection.

Immunoglobulins have also been used in Rasmussen’s as well immune mediated encephalitis ³²⁾. IVIg is a purified blood product pooled from many human donors composed mainly of IgG and some IgA. The precise mode of action of this product is unclear. Several studies have shown efficacy in treating patients with immunodeficiency. The use in patients with epilepsy has increased given the identification of immune mediated epilepsy but Cochrane reviews show no randomized evidence outside of specific syndromes such as anti NMDA and Landau Kleffner ³³⁾.

Steroid, immunoglobulins and other anti-inflammatory agent are also increasingly used in immune epilepsy. If these agents are to be used it would be important to Identify potential patients who have an immune basis for their seizures because adjunctive immunotherapy may slow, halt, or even reverse the epileptogenic process.

Zuliani ³⁴⁾ and Suleiman ³⁵⁾ have proposed guidelines for recognition of these patients in adults and children respectively. Clinical features suggestive of an autoimmune pathogenesis include patients with recent onset epilepsy (< 2 years), early antiepileptic drug resistance, and multifocal seizures and personal or family history of autoimmunity. Paraclinical findings suggestive of an autoimmune etiology include the detection of a neural autoantibody, inflammatory CSF (leukocytosis or CSF-exclusive oligoclonal immunoglobulin bands), or MRI characteristics suggesting inflammation (T2 hyperintensities, contrast enhancement on gadolinium studies, and/or restricted diffusion) and /or inflammatory neuropathology on biopsy.

Recurrent seizures are a common symptom in autoimmune neurologic disorders, especially in limbic encephalitis or multifocal paraneoplastic disorders. Autoantibody specificities reported in the setting of paraneoplastic limbic encephalitis include antineuronal nuclear antibody type 1 (ANNA-1), collapsin response-mediator protein 5 (CRMP-5), and Ma2. Autoantibodies with a commonly nonparaneoplastic etiology include Voltage-gated potassium channel (VGKC) complex or associated proteins including leucinerich glioma inactivated 1 (LGI1), contactin-associated protein 2 (CASPR2) and contactin 2 and glutamic acid decarboxylase 65 (GAD65) antibodies and have been reported in patients with limbic encephalitis and idiopathic epilepsy with antiepileptic drug-resistant seizures. More recently identified autoantibodies that strongly correlate with clinical seizures include N -methyl-D-aspartate receptor (NMDAR), 23 γ-aminobutyric acid B (GABAB) receptor, metabotropic glutamate receptor type 5 (mGluR5) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors.

No randomized clinical control trials on the use of corticosteroids in autoimmune epilepsies have been conducted to date. In an observational, retrospective case series by Quek et al. ³⁶⁾, neural autoantibodies were identified in 29/32 patients (91%). VGKC complex IgG antibodies were detected in 18/29 (62%) of which 14 were bound to LGI1 (78%), 1 was bound to Caspr2 and 3 were of unknown specificity. In addition, GAD65 was found in 7/29 (24%), and CRMP-5 was found in 2/29. In this study, 27 people underwent immunosuppressive treatment that comprised intravenous methylprednisolone alone (IVMP) (n = 12); intravenous immune globulin alone (IVIg) (n = 3); and combinations of IVMP, intravenous immune globulin alone (IVIg), cyclophosphamide, or plasmapheresis (n = 12). In 22/27 patients (81%), this therapeutic trial was positive with 18 patients becoming seizure free for at least 3 months and 4 patients having improved seizure frequency. Early treatment was associated with a favorable outcome.

Although strong evidence is lacking, the authors recommended that if autoimmune epilepsy is suspected, a trial of 6 to 12 weeks of immunotherapy (intravenous methylprednisolone or IVIg daily for 3 days and then weekly) is justifiable in the absence of other treatment options and may serve as additional evidence for an autoimmune etiology when a favorable seizure response is observed. They also recommended considering long-term immunosuppressive treatment, overlapping with gradual taper of intravenous methylprednisolone or IVIg, for patients whose seizures respond favorably to the initial trial of immunotherapy. Despite this, relapses may still occur.

Clinical trials

If other treatments don’t work or you are interested in exploring new therapies, taking part in an experimental clinical trial should be considered (https://www.epilepsy.com/clinical_trials). These trials may test a new medication, device, or surgical procedure that has not been approved by the FDA yet. Or there may be trials testing how well approved medications or therapies works compared to others.

Clinical research is also done to better understand the problems associated with uncontrolled epilepsy or how complementary therapies, such as diet, stress management, or safety devices may help.

While new therapies are developed by clinical trials, people need to be aware that they are participating in research. Supervision and safety controls are extensive, but there still is an element of risk and the unknown. If a trial is successful, you may get to use a new therapy years before it becomes available to the public.

Intractable epilepsy prognosis

Intractable epilepsy does not always remain intractable. First, one of the treatments listed above may prove effective. Second, individuals may be able to modify precipitating factors or their lifestyle to help to control the seizures. But even in the absence of specific therapies or life changes, there is hope for improvement. Jacqueline French and associates studied 246 patients from their clinic who had at least one seizure per month and were taking at least two seizure medications. Over a three-year follow-up period, 5% of these patients each year became seizure-free for at least six months. Unfavorable predictors of control were chronic cognitive delay, long history of intractable seizures and previous status epilepticus.

Despite the hope that some people will get better over time, you must also remember that uncontrolled seizures bring a number of other problems. People living with active seizures have greater risks of accidents, injuries, cognitive problems, mood disorders, social problems, unemployment and more. Unfortunately, serious and life-threatening risks of seizures are real. Understanding the causes and seriousness of uncontrolled epilepsy may help people get the right help as early as possible.

What is cerebral palsy

Cerebral palsy is a group of neurological disorders caused by non-progressive brain damage in the area that controls muscle tone (the motor cortex) resulting from an insult (adverse effect) in the time before birth (prenatal), during birth (perinatal) or shortly after birth (postnatal). In some cases, the motor cortex fails to develop normally in the fetus. This nervous system damage affects a person’s motor skills (ability to coordinate body movements), posture, balance and muscle tone. Cerebral palsy often shows up as either floppy or stiff muscles, or involuntary muscle movements.

Cerebral palsy is not hereditary. Depending on the damage, cerebral palsy affects people in different ways and to different extents.

Cerebral palsy can affect movement, coordination, muscle tone and posture. Cerebral palsy can also be associated with impaired vision, hearing, speech, eating and learning.

The majority of children with cerebral palsy are born with it, although it may not be detected until months or years later. Children with cerebral palsy tend to miss developmental milestones such as crawling, walking and talking. Usually, a confirmed diagnosis of cerebral palsy is made by the time a child is 2.

Cerebral palsy is a common problem, occurring in about 2 to 2.5 per 1,000 live births. The occurence of cerebral palsy is slowly increasing most probably because of the improved survival rates of pre-term infants. More than 100,000 Americans under the age of 18 years are estimated to have some degree of neurologic impairment associated with cerebral palsy.

There are four main types of cerebral palsy:

1. Spastic cerebral palsy is characterized by increased muscle tone, resulting in stiffness of affected limbs;
2. Athetoid cerebral palsy is characterized by involuntary movements;
3. Ataxic cerebral palsy occurs when the cerebellum (part of the brain) has been damaged, thus causing lack of coordination and jerky movements;
4. Infantile hemiparesis is characterized by seizures and one side of the body being affected more than the other.

Cerebral palsy may also be mixed, with components of 2 or more of the above. Spastic cerebral palsy is the most common type of cerebral palsy and in present in about 50% of people with cerebral palsy.

The early signs of cerebral palsy usually appear before a child reaches 3 years of age. The most common are:

• a lack of muscle coordination when performing voluntary movements (ataxia);
• stiff or tight muscles and exaggerated reflexes (spasticity);
• walking with one foot or leg dragging;
• walking on the toes, a crouched gait, or a “scissored” gait; and
• muscle tone that is either too stiff or too floppy.

Other neurological symptoms that commonly occur in individuals with cerebral palsy include seizures, hearing loss, problems swallowing, eye muscle imbalance (in which the eyes don’t focus on the same object) and impaired vision, bladder and bowel control issues, and pain and abnormal sensations. People with cerebral palsy also may suffer reduced range of motion at various joints of their bodies due to muscle stiffness.

Cerebral palsy’s effect on functional abilities varies greatly. Some affected people can walk while others can’t. Some people show normal or near-normal intellectual capacity, but others may have intellectual disabilities. Epilepsy, blindness or deafness also may be present.

The causes of cerebral palsy may be multiple but in most the precise cause of damage in an individual child may be difficult to determine. Current evidence suggests that events during pregnancy are responsible for 70-80% of cases of cerebral palsy. Factors such as prematurity, exposure to toxins and infections, congenital abnormalities may influence the risk of developing cerebral palsy. Maternal factors such as pre-existing disease, previous pregnancy loss, and complications during pregnancy and birth are also thought to be important.

A small number of children have cerebral palsy as the result of brain damage in the first few months or years of life, brain infections such as bacterial meningitis or viral encephalitis, or head injury from a motor vehicle accident, a fall, or child abuse. The disorder isn’t progressive, meaning that the brain damage typically doesn’t get worse over time. Risk factors associated with cerebral palsy do not cause the disorder but can increase a child’s chance of being born with the disorder.

If you think your child is showing some of the symptoms of cerebral palsy, or their development may be delayed, see your early childhood nurse or healthcare provider.

Types of cerebral palsy

Several cerebral palsy classification systems exist today to define the type and form of cerebral palsy an individual has. The classification is complicated by the wide range of clinical presentations and degrees of activity limitation that exist ¹⁾. Knowing the severity, location and type of cerebral palsy your child has will help to coordinate care and fund treatment.

Medical professionals who specialize in the treatment of cerebral palsy approach the condition from a number of different vantage points. An orthopedic surgeon requires a definition of the limbs affected and the extent of impairment in order to prescribe treatment.

Neurosurgeons and neuroradiologists, on the other hand, are more concerned with the cause of the brain damage and descriptors for imposing white and gray matter so as to determine the type of brain injury or brain malformation. They are also concerned with diagnosing the extent and severity level of the child’s cerebral palsy.

At first, a parent may be concerned with the severity level classification – mild, moderate or severe – in order to better understand the seriousness of the child’s impairment or disability. When meeting with the child’s pediatrician or physical therapist, it is useful to understand the topographical distribution of the impairment – the limbs and the sides of the body affected by brain damage. It is also important to clarify whether the child has a plegia (paralysis) or paresis (weakened) condition.

Government agencies and school administrators may be more concerned with classification systems that coincide with their ability to qualify a child for special education supports and services. Only then can they plan and administer and allocate educational supports to the child.

Researchers are interested in utilizing a universally accepted classification system, such as the Gross Motor Function Classification System, or GMFCS, to increase consistency in studies worldwide and to expand the ability to build knowledge around prevalence, life expectancy, societal impact, prevention measures and educational awareness.

For these reasons, many cerebral palsy classification systems are used today. Over the last 150 years, the definition of cerebral palsy has evolved and changed as new medical discoveries contributed to growing knowledge of the condition. Although a myriad of classifications – used differently and for many purposes – exists today, those involved in cerebral palsy research are working toward a universally accepted classification system.

Because of the diversity of classification systems, parents may want to document different terms doctors use in cerebral palsy diagnosis. In addition, parents should also maintain home health records documenting associated impairments, anatomic and radiation findings, as well as causation and timing. MyChild has developed the Cerebral Palsy Diagnosis Checklist (https://www.cerebralpalsy.org/about-cerebral-palsy/diagnosis/checklist) and the Cerebral Palsy Risk Factor Checklist (https://www.cerebralpalsy.org/about-cerebral-palsy/risk-factors/checklist) for this purpose.

Below are the most commonly used classification systems understood and used by qualified medical practitioners ²⁾:

1. Classification based on severity level
2. Classification based on topographical distribution
3. Classification based on motor function
4. Classification based on gross motor function classification system

Cerebral palsy classification based on severity level

Cerebral palsy is often classified by severity level as mild, moderate, severe, or no cerebral palsy. These are broad generalizations that lack a specific set of criteria.

Even when doctors agree on the level of severity, the classification provides little specific information, especially when compared to the GMFCS. Still, this method is common and offers a simple method of communicating the scope of impairment, which can be useful when accuracy is not necessary.

• Mild cerebral palsy – Mild cerebral palsy means a child can move without assistance; his or her daily activities are not limited.
• Moderate cerebral palsy – Moderate cerebral palsy means a child will need braces, medications, and adaptive technology to accomplish daily activities.
• Severe cerebral palsy – Severe cerebral palsy means a child will require a wheelchair and will have significant challenges in accomplishing daily activities.
• No cerebral palsy – No cerebral palsy means the child has cerebral palsy signs, but the impairment was acquired after completion of brain development and is therefore classified under the incident that caused the Cerebral Palsy, such as traumatic brain injury or encephalopathy.

Cerebral palsy classification based on topographical distribution

Topographical classification describes body parts affected. The words are a combination of phrases combined for one single meaning. When used with Motor Function Classification System, it provides a description of where and to what extent a child is affected by Cerebral Palsy. This method is useful in ascertaining treatment protocol.

• Paresis means weakened
• Plegia or Plegic means paralyzed

The prefixes and root words are combined to yield the topographical classifications commonly used in practice today.

• Monoplegia or monoparesis means only one limb is affected. It is believed this may be a form of hemiplegia/hemiparesis where one limb is significantly impaired.
• Diplegia or diparesis usually indicates the legs are affected more than the arms; primarily affects the lower body.
• Hemiplegia or hemiparesis indicates the arm and leg on one side of the body are affected.
• Paraplegia or paraparesis means the lower half of the body, including both legs, is affected.
• Triplegia or triparesis indicates three limbs are affected. This could be both arms and a leg, or both legs and an arm. Or, it could refer to one upper and one lower extremity and the face.
• Double hemiplegia or double hemiparesis indicates all four limbs are involved, but one side of the body is more affected than the other.
• Tetraplegia or tetraparesis indicates that all four limbs are involved, but three limbs are more affected than the fourth.
• Quadriplegia or quadriparesis means that all four limbs are involved.
• Pentaplegia or pentaparesis means all four limbs are involved, with neck and head paralysis often accompanied by eating and breathing complications

Cerebral palsy classification based on motor function

The brain injury that causes cerebral palsy affects motor function, the ability to control the body in a desired matter.

Motor function classification provides both a description of how a child’s body is affected and the area of the brain injury. Using motor function gives parents, doctors, and therapists a very specific, yet broad, description of a child’s symptoms, which helps doctors choose treatments with the best chance for success.

Two main groupings include spastic cerebral palsy (pyramidal cerebral palsy) and  non-spastic cerebral palsy (extrapyramidal cerebral palsy). Each has multiple variations and it is possible to have a mixture of both types.

1. Spastic cerebral palsy (pyramidal cerebral palsy) is characterized by increased muscle tone.
2. Non-spastic cerebral palsy (extrapyramidal cerebral palsy) will exhibit decreased or fluctuating muscle tone.

Muscle tone

Many motor function terms describe cerebral palsy’s effect on muscle tone and how muscles work together. Proper muscle tone when bending an arm requires the bicep to contract and the triceps to relax. When muscle tone is impaired, muscles do not work together and can even work in opposition to one another.

Two terms used to describe muscle tone are:

1. Hypertonia or hypertonic — increased muscle tone, often resulting in very stiff limbs. Hypertonia is associated with spastic Cerebral Palsy
2. Hypotonia or hypotonic — decreased muscle tone, often resulting in loose, floppy limbs. Hypotonia is associated with non-spastic Cerebral Palsy

Two classifications by motor function:

When referring to location of the brain injury, spastic and non-spastic cerebral palsy is referred to in the medical community as pyramidal and extrapyramidal cerebral palsy.

Spastic cerebral palsy or pyramidal cerebral palsy

The pyramidal tract consists of two groups of nerve fibers responsible for voluntary movements. They descend from the cortex into the brain stem. In essence, they are responsible for communicating the brain’s movement intent to the nerves in the spinal cord that will stimulate the event. Pyramidal Cerebral Palsy would indicate that the pyramidal tract is damaged or not functioning properly.

Extrapyramidal cerebral palsy indicates the injury is outside the tract in areas such as the basal ganglia, thalamus, and cerebellum. Pyramidal and extrapyramidal are key components to movement impairments.

Spasticity implies increased muscle tone. Muscles continually contract, making limbs stiff, rigid, and resistant to flexing or relaxing. Reflexes can be exaggerated, while movements tend to be jerky and awkward. Often, the arms and legs are affected. The tongue, mouth, and pharynx can be affected, as well, impairing speech, eating, breathing, and swallowing.

Spastic cerebral palsy is hypertonic and accounts for 70% to 80% of Cerebral Palsy cases. The injury to the brain occurs in the pyramidal tract and is referred to as upper motor neuron damage.

The stress on the body created by spasticity can result in associated conditions such as hip dislocation, scoliosis, and limb deformities. One particular concern is contracture, the constant contracting of muscles that results in painful joint deformities.

Spastic cerebral palsy is often named in combination with a topographical method that describes which limbs are affected, such as spastic diplegia, spastic hemiparesis, and spastic quadriplegia.

Non-spastic cerebral palsy or extrapyramidal cerebral palsy

Non-spastic cerebral palsy is decreased and/or fluctuating muscle tone. Multiple forms of non-spastic cerebral palsy are each characterized by particular impairments; one of the main characteristics of non-spastic cerebral palsy is involuntary movement. Movement can be slow or fast, often repetitive, and sometimes rhythmic. Planned movements can exaggerate the effect – a condition known as intention tremors. Stress can also worsen the involuntary movements, whereas sleeping often eliminates them.

An injury in the brain outside the pyramidal tract causes non-spastic cerebral palsy. Due to the location of the injury, mental impairment and seizures are less likely. Non-spastic Cerebral Palsy lowers the likelihood of joint and limb deformities. The ability to speak may be impaired as a result of physical, not intellectual, impairment.

Non-spastic cerebral palsy is divided into two groups, ataxic and dyskinetic. Together they make up 20% of Cerebral Palsy cases. Broken down, dyskinetic makes up 15% of all Cerebral Palsy cases, and ataxic comprises 5%.

Ataxic or ataxia

Ataxic cerebral palsy affects coordinated movements. Balance and posture are involved. Walking gait is often very wide and sometimes irregular. Control of eye movements and depth perception can be impaired. Often, fine motor skills requiring coordination of the eyes and hands, such as writing, are difficult. Does not produce involuntary movements, but instead indicates impaired balance and coordination

Dyskinetic

Dyskinetic cerebral palsy is separated further into two different groups; athetoid and dystonic.

1. Athetoid cerebral palsy includes cases with involuntary movement, especially in the arms, legs, and hands.
2. Dystonia or dystonic cerebral palsy encompasses cases that affect the trunk muscles more than the limbs and results in fixed, twisted posture.

Because non-spastic cerebral palsy is predominantly associated with involuntary movements, some may classify cerebral palsy by the specific movement dysfunction, such as:

• Athetosis — slow, writhing movements that are often repetitive, sinuous, and rhythmic
• Chorea — irregular movements that are not repetitive or rhythmic, and tend to be more jerky and shaky
• Chorea — irregular movements that are not repetitive or rhythmic, and tend to be more jerky and shaky
• Choreoathetoid — a combination of chorea and athetosis; movements are irregular, but twisting and curving
• Dystonia — involuntary movements accompanied by an abnormal, sustained posture
• Mixed – a child’s impairments can fall into both categories, spastic and non-spastic, referred to as mixed Cerebral Palsy. The most common form of mixed Cerebral Palsy involves some limbs affected by spasticity and others by athetosis.

Cerebral palsy classification based on Gross Motor Function Classification System

Gross Motor Function Classification System or GMFCS (http://templatelab.com/GMFCS-ER), uses a five-level system that corresponds to the extent of ability and impairment limitation. A higher number indicates a higher degree of severity. Each level is determined by an age range and a set of activities the child can achieve on his or her own.

The Gross Motor Function Classification System is a universal classification system applicable to all forms of cerebral palsy. Using Gross Motor Function Classification System helps determine the surgeries, treatments, therapies, and assistive technology likely to result in the best outcome for a child. Additionally, the Gross Motor Function Classification System is a powerful system for researchers; it improves data collection and analysis and hence result in better understanding and treatment of cerebral palsy.

The Gross Motor Function Classification System addresses the goal set by organizations such as the World Health Organization (WHO) and the Surveillance of Cerebral Palsy in Europe, which advocate for a universal classification system that focuses on what a child can accomplish, as opposed to the limitations imposed by his or her impairments.

The Gross Motor Function Classification System is useful to parents and caretakers as a developmental guideline which takes into consideration the child’s motor impairment. It assigns a classification level (GMFCS Level 1 – 5). The parent is then able to understand motor impairment abilities over time, as the child progresses in age.

To best utilize the Gross Motor Function Classification System, it is often combined with other classification systems that define the extent, location, and severity of impairment. It is also recommended to document upper extremity function and speech impairments.

The Gross Motor Function Classification System uses head control, movement transition, walking, and gross motor skills such as running, jumping, and navigating inclined or uneven surfaces to define a child’s accomplishment level. The goal is to present an idea of how self-sufficient a child can be at home, at school, and at outdoor and indoor venues.

When the child fits in multiple levels, the lower of the two classification levels is chosen. The GMFCS classification system recognizes that children with impairments have age-appropriate developmental factors. Gross Motor Function Classification System is able to chart by age group (0-2; 2-4; 4-6; 6-12; and 12-18) a developmental guideline appropriate for the assigned GMFCS level. It emphasizes sitting, movement transfers and mobility, charting independence and reliance on adaptive technology.

Cerebral Palsy is often classified by severity level as mild, moderate, severe, or no cerebral palsy. These are broad generalizations that lack a specific set of criteria. Even when doctors agree on the level of severity, the classification provides little specific information, especially when compared to the Gross Motor Function Classification System. Still, this method is common and offers a simple method of communicating the scope of impairment, which can be useful when accuracy is not necessary.

Gross Motor Function Classification System classification levels

• GMFCS Level 1 – walks without limitations.
• GMFCS Level 2 – walks with limitations. Limitations include walking long distances and balancing, but not as able as Level I to run or jump; may require use of mobility devices when first learning to walk, usually prior to age 4; and may rely on wheeled mobility equipment when outside of home for traveling long distances.
• GMFCS Level 3 – walks with adaptive equipment assistance. Requires hand-held mobility assistance to walk indoors, while utilizing wheeled mobility outdoors, in the community and at school; can sit on own or with limited external support; and has some independence in standing transfers.
• GMFCS Level 4 – self-mobility with use of powered mobility assistance. Usually supported when sitting; self-mobility is limited; and likely to be transported in manual wheelchair or powered mobility.
• GMFCS Level 5 – severe head and trunk control limitations. Requires extensive use of assisted technology and physical assistance; and transported in a manual wheelchair, unless self-mobility can be achieved by learning to operate a powered wheelchair.

[Source ³⁾ ]

Cerebral palsy prognosis

Cerebral palsy doesn’t always cause profound disabilities and for most people with cerebral palsy the disorder have a normal life expectancy. Many children with cerebral palsy have average to above average intelligence and attend the same schools as other children their age.

On the other hand, some patients who have severe cerebral palsy have a reduced life span. The severity of the cerebral palsy and its associated complications will affect prognosis. Patients with paralysis of all four limbs (quadriplegia), severe intellectual impairment and epilepsy have a worse outcome.

Supportive treatments, medications, and surgery can help many individuals improve their motor skills and ability to communicate with the world. While one child with cerebral palsy might not require special assistance, a child with severe cerebral palsy might be unable to walk and need extensive, lifelong care.

Approximately one quarter of cerebral palsy patients will have minimal or no functional limitation. Half will be moderately impaired and although their functional capacity will be satisfactory, achieving complete independence is unlikely. The remaining quarter will be severely disabled and require full time care.

Cerebral palsy complications

Muscle weakness, muscle spasticity and coordination problems can contribute to a number of complications either during childhood or later during adulthood, including:

• Contracture. Contracture is muscle tissue shortening due to severe muscle tightening (spasticity). Contracture can inhibit bone growth, cause bones to bend, and result in joint deformities, dislocation or partial dislocation.
• Malnutrition. Swallowing or feeding problems can make it difficult for someone who has cerebral palsy, particularly an infant, to get enough nutrition. This may cause impaired growth and weaker bones. Some children may need a feeding tube for adequate nutrition.
• Mental health conditions. People with cerebral palsy may have mental health (psychiatric) conditions, such as depression. Social isolation and the challenges of coping with disabilities can contribute to depression.
• Lung disease. People with cerebral palsy may develop lung disease and breathing disorders.
• Neurological conditions. People with cerebral palsy may be more likely to develop movement disorders or worsened neurological symptoms over time.
• Osteoarthritis. Pressure on joints or abnormal alignment of joints from muscle spasticity may lead to the early onset of painful degenerative bone disease (osteoarthritis).
• Osteopenia. Fractures due to low bone density (osteopenia) can stem from several common factors such as lack of mobility, nutritional shortcomings and antiepileptic drug use.
• Eye muscle imbalance. This can affect visual fixation and tracking; an eye specialist should evaluate suspected imbalances.

Cerebral palsy causes

The cause remains unknown for most babies with cerebral palsy. There is no single cause of cerebral palsy.

The damage to the brain does not worsen with age, but it’s permanent. There is no cure. Life expectancy is normal, but the effects of cerebral palsy can cause stress to the body and premature ageing.

Cerebral palsy is caused by an abnormality or disruption in brain development, usually before a child is born. In many cases, the exact trigger isn’t known.

Factors that may lead to problems with brain development include:

• Mutations in genes that lead to abnormal brain development
• Maternal infections that affect the developing fetus
• Fetal stroke, a disruption of blood supply to the developing brain
• Infant infections that cause inflammation in or around the brain
• Traumatic head injury to an infant from a motor vehicle accident or fall
• Lack of oxygen to the brain (asphyxia) related to difficult labor or delivery, although birth-related asphyxia is much less commonly a cause than historically thought

Risk factors for cerebral palsy

A number of factors are associated with an increased risk of cerebral palsy.

Maternal health

Certain infections or health problems during pregnancy can significantly increase cerebral palsy risk to the baby. Infections of particular concern include:

• German measles (rubella). Rubella is a viral infection that can cause serious birth defects. It can be prevented with a vaccine.
• Chickenpox (varicella). Chickenpox is a contagious viral infection that causes itching and rashes, and it can cause pregnancy complications. It too can be prevented with a vaccine.
• Cytomegalovirus. Cytomegalovirus is a common virus that causes flu-like symptoms and may lead to birth defects if a mother experiences her first active infection during pregnancy.
• Herpes. Herpes infection can be passed from mother to child during pregnancy, affecting the womb and placenta. Inflammation triggered by infection may then damage the unborn baby’s developing nervous system.
• Toxoplasmosis. Toxoplasmosis is an infection caused by a parasite found in contaminated food, soil and the feces of infected cats.
• Syphilis. Syphilis is a sexually transmitted bacterial infection.
• Exposure to toxins. Exposure to toxins, such as methyl mercury, can increase the risk of birth defects.
• Zika virus infection. Infants for whom maternal Zika infection causes microcephaly can develop cerebral palsy.
• Other conditions. Other conditions may increase the risk of cerebral palsy, such as thyroid problems, intellectual disabilities or seizures.

Infant illness

Illnesses in a newborn baby that can greatly increase the risk of cerebral palsy include:

• Bacterial meningitis. This bacterial infection causes inflammation in the membranes surrounding the brain and spinal cord.
• Viral encephalitis. This viral infection similarly causes inflammation in the membranes surrounding the brain and spinal cord.
• Severe or untreated jaundice. Jaundice appears as a yellowing of the skin. The condition occurs when certain byproducts of “used” blood cells aren’t filtered from the bloodstream.

Other factors of pregnancy and birth

While the potential contribution from each is limited, additional pregnancy or birth factors associated with increased cerebral palsy risk include:

• Breech births. Babies with cerebral palsy are more likely to be in a feet-first position (breech presentation) at the beginning of labor rather than headfirst.
• Complicated labor and delivery. Babies who exhibit vascular or respiratory problems during labor and delivery may have existing brain damage or abnormalities.
• Low birth weight (birth weight less than 1,500 grams). Babies who weigh less than 5.5 pounds (2.5 kilograms) are at higher risk of developing cerebral palsy. This risk increases as birth weight drops.
• Multiple babies (twins, triplets, etc.). Cerebral palsy risk increases with the number of babies sharing the uterus. If one or more of the babies die, the chance that the survivors may have cerebral palsy increases.
• Premature birth. A normal pregnancy lasts 40 weeks. Babies born fewer than 37 weeks into the pregnancy are at higher risk of cerebral palsy. The earlier a baby is born, the greater the cerebral palsy risk.
• Rh blood type incompatibility between mother and child. If a mother’s Rh blood type doesn’t match her baby’s, her immune system may not tolerate the developing baby’s blood type and her body may begin to produce antibodies to attack and kill her baby’s blood cells, which can cause brain damage.

Cerebral palsy prevention

Most cases of cerebral palsy can’t be prevented, but you can lessen risks. If you’re pregnant or planning to become pregnant, you can take these steps to keep healthy and minimize pregnancy complications:

• Make sure you’re vaccinated. Vaccination against diseases such as rubella may prevent an infection that could cause fetal brain damage.
• Take care of yourself. The healthier you are heading into a pregnancy, the less likely you’ll be to develop an infection that may result in cerebral palsy.
• Seek early and continuous prenatal care. Regular visits to your doctor during your pregnancy are a good way to reduce health risks to you and your unborn baby. Seeing your doctor regularly can help prevent premature birth, low birth weight and infections.
• Practice good child safety. Prevent head injuries by providing your child with a car seat, bicycle helmet, safety rails on beds and appropriate supervision.

Cerebral palsy symptoms

Signs and symptoms can vary greatly. Movement and coordination problems associated with cerebral palsy may include:

• Variations in muscle tone, such as being either too stiff or too floppy
• Stiff muscles and exaggerated reflexes (spasticity)
• Stiff muscles with normal reflexes (rigidity)
• Lack of muscle coordination (ataxia)
• Tremors or involuntary movements
• Slow, writhing movements (athetosis)
• Delays in reaching motor skills milestones, such as pushing up on arms, sitting up alone or crawling
• Favoring one side of the body, such as reaching with only one hand or dragging a leg while crawling
• Difficulty walking, such as walking on toes, a crouched gait, a scissors-like gait with knees crossing, a wide gait or an asymmetrical gait
• Excessive drooling or problems with swallowing
• Difficulty with sucking or eating
• Delays in speech development or difficulty speaking
• Difficulty with precise motions, such as picking up a crayon or spoon
• Seizures

The disability associated with cerebral palsy may be limited primarily to one limb or one side of the body, or it may affect the whole body. The brain disorder causing cerebral palsy doesn’t change with time, so the symptoms usually don’t worsen with age. However, muscle shortening and muscle rigidity may worsen if not treated aggressively.

Brain abnormalities associated with cerebral palsy also may contribute to other neurological problems. People with cerebral palsy may also have:

• Difficulty with vision and hearing
• Intellectual disabilities
• Seizures
• Abnormal touch or pain perceptions
• Oral diseases
• Mental health (psychiatric) conditions
• Urinary incontinence.

Cerebral palsy diagnosis

If your family doctor or pediatrician suspects your child has cerebral palsy, he or she will evaluate your child’s signs and symptoms, review your child’s medical history, and conduct a physical evaluation. Your doctor may refer you to a specialist trained in treating children with brain and nervous system conditions (pediatric neurologist).

Your doctor will also order a series of tests to make a diagnosis and rule out other possible causes.

Brain scans

Brain-imaging technologies can reveal areas of damage or abnormal development in the brain. These tests may include the following:

• Magnetic resonance imaging (MRI). An MRI uses radio waves and a magnetic field to produce detailed 3-D or cross-sectional images of your child’s brain. An MRI can often identify any lesions or abnormalities in your child’s brain. This test is painless, but it’s noisy and can take up to an hour to complete. Your child will likely receive a mild sedative beforehand. An MRI is usually the preferred imaging test.
• Cranial ultrasound. This can be performed during infancy. A cranial ultrasound uses high-frequency sound waves to obtain images of the brain. An ultrasound doesn’t produce a detailed image, but it may be used because it’s quick and inexpensive, and it can provide a valuable preliminary assessment of the brain.

Electroencephalogram (EEG)

If your child has had seizures, your doctor may order an electroencephalogram (EEG) to determine if he or she has epilepsy, which often occurs in people with cerebral palsy. In an EEG test, a series of electrodes are affixed to your child’s scalp.

The EEG records the electrical activity of your child’s brain. If he or she has epilepsy, it’s common for there to be changes in normal brain wave patterns.

Laboratory tests

Laboratory tests may also screen for genetic or metabolic problems.

Additional tests

If your child is diagnosed with cerebral palsy, you’ll likely be referred to specialists for assessments of other conditions often associated with the disorder. These tests may identify:

• Vision impairment
• Hearing impairment
• Speech delays or impairments
• Intellectual disabilities
• Other developmental delays
• Movement disorders.

Cerebral palsy treatment

While there is no cure for cerebral palsy, many things can be done to improve the quality of the life for the person with cerebral palsy and their family. This includes the treatment of seizures with anticonvulsant medications, medications to reduce muscle stiffness and control involuntary movements.

In general, the earlier treatment begins the better chance children have of overcoming developmental disabilities or learning new ways to accomplish the tasks that challenge them. Early intervention, supportive treatments, medications, and surgery can help many individuals improve their muscle control. Treatment may include physical and occupational therapy, speech therapy, drugs to control seizures, relax muscle spasms, and alleviate pain; surgery to correct anatomical abnormalities or release tight muscles; braces and other orthotic devices; wheelchairs and rolling walkers; and communication aids such as computers with attached voice synthesizers.

Physiotherapy and massage may be important in maintaining a range of movement and muscle strength, and occupational therapy can be invaluable in helping a child affected by cerebral palsy to develop skills needed for daily living. In the case of severe muscle spasticity, surgery may be a valuable option. Tendon release procedures, usually performed by an orthopedic surgeon, allow improved range of motion in some cases.

Children and adults with cerebral palsy require long-term care with a medical care team. This team may include:

• Physical medicine and rehabilitation physician or physiatrist. A physiatrist oversees the treatment plan and medical care.
• Pediatric neurologist. A doctor trained to diagnose and treat children with brain and nervous system (neurological) disorders may be involved in your child’s care.
• Orthopedic surgeon. A doctor trained to treat muscle and bone disorders may be involved to diagnose and treat muscle conditions.
• Physical therapist. A physical therapist may help your child improve strength and walking skills, and stretch muscles.
• Occupational therapist. An occupational therapist can provide therapy to your child to develop daily skills and to learn to use adaptive products that help with daily activities.
• Speech-language pathologist. A doctor trained to diagnose and treat speech and language disorders may work with your child if your child suffers from speech, swallowing or language difficulties.
• Developmental therapist. A developmental therapist may provide therapy to help your child develop age-appropriate behaviors, social skills and interpersonal skills.
• Mental health specialist. A mental health specialist, such as a psychologist or psychiatrist, may be involved in your child’s care. He or she may help you and your child learn to cope with your child’s disability.
• Recreation therapist. Participation in art and cultural programs, sports, and other events that help children expand physical and cognitive skills and abilities. Parents of children often note improvements in a child’s speech, self-esteem and emotional well-being.
• Social worker. A social worker may assist your family to find services and plan for care transitions.
• Special education teacher. A special education teacher addresses learning disabilities, determines educational needs and identifies appropriate educational resources.

Medications

Medications that can lessen the tightness of muscles may be used to improve functional abilities, treat pain and manage complications related to spasticity or other cerebral palsy symptoms.

It’s important to talk about drug treatment risks with your doctor and discuss whether medical treatment is appropriate for your child’s needs. Medication selection depends on whether the problem affects only certain muscles (isolated) or the whole body (generalized). Drug treatments may include the following:

• Isolated spasticity. When spasticity is isolated to one muscle group, your doctor may recommend onabotulinumtoxinA (Botox) injections directly into the muscle, nerve or both. Botox injections may help to improve drooling. Your child will need injections about every three months. Side effects may include pain, mild flu-like symptoms, bruising or severe weakness. Other more-serious side effects include difficulty breathing and swallowing.
• Generalized spasticity. If the whole body is affected, oral muscle relaxants may relax stiff, contracted muscles. These drugs include diazepam (Valium), dantrolene (Dantrium) and baclofen (Gablofen). Diazepam carries some dependency risk, so it’s not recommended for long-term use. Its side effects include drowsiness, weakness and drooling. Dantrolene side effects include sleepiness, weakness, nausea and diarrhea. Baclofen side effects include sleepiness, confusion and nausea. Note that baclofen may also be pumped directly into the spinal cord with a tube. The pump is surgically implanted under the skin of the abdomen.

Your child also may be prescribed medications to reduce drooling. Medications such as trihexyphenidyl, scopolamine or glycopyrrolate (Robinul, Robinul Forte) may be helpful, as can Botox injection into the salivary glands.

Therapies

A variety of nondrug therapies can help a person with cerebral palsy enhance functional abilities:

• Physical therapy. Muscle training and exercises may help your child’s strength, flexibility, balance, motor development and mobility. You’ll also learn how to safely care for your child’s everyday needs at home, such as bathing and feeding your child. For the first 1 to 2 years after birth, both physical and occupational therapists provide support with issues such as head and trunk control, rolling, and grasping. Later, both types of therapists are involved in wheelchair assessments. Braces or splints may be recommended for your child. Some of these supports help with function, such as improved walking. Others may stretch stiff muscles to help prevent rigid muscles (contractures).
• Occupational therapy. Using alternative strategies and adaptive equipment, occupational therapists work to promote your child’s independent participation in daily activities and routines in the home, the school and the community. Adaptive equipment may include walkers, quadrupedal canes, seating systems or electric wheelchairs.
• Speech and language therapy. Speech-language pathologists can help improve your child’s ability to speak clearly or to communicate using sign language. Speech-language pathologists can also teach your child to use communication devices, such as a computer and voice synthesizer, if communication is difficult. Another communication device may be a board covered with pictures of items and activities your child may see in daily life. Sentences can be constructed by pointing to the pictures. Speech therapists may also address difficulties with muscles used in eating and swallowing.
• Recreational therapy. Some children may benefit from recreational therapies, such as therapeutic horseback riding. This type of therapy can help improve your child’s motor skills, speech and emotional well-being.

Surgical or other procedures

Surgery may be needed to lessen muscle tightness or correct bone abnormalities caused by spasticity. These treatments include:

• Orthopedic surgery. Children with severe contractures or deformities may need surgery on bones or joints to place their arms, hips or legs in their correct positions. Surgical procedures can also lengthen muscles and tendons that are proportionally too short because of severe contractures. These corrections can lessen pain and improve mobility. The procedures may also make it easier to use a walker, braces or crutches.
• Severing nerves. In some severe cases, when other treatments haven’t helped, surgeons may cut the nerves serving the spastic muscles in a procedure called selective dorsal rhizotomy. This relaxes the muscle and reduces pain, but can also cause numbness.

Coping and support

When a child is diagnosed with a disabling condition, the whole family faces new challenges. Here are a few tips for caring for your child and yourself:

• Foster your child’s independence. Encourage any effort at independence, no matter how small. Just because you can do something faster or more easily than your child doesn’t mean you should.
  Be an advocate for your child. You are an important part of your child’s health care team. Don’t be afraid to speak out on your child’s behalf or to ask tough questions of your physicians, therapists and teachers.
• Find support. A circle of support can make a big difference in helping you cope with cerebral palsy and its effects. As a parent, you may feel grief and guilt over your child’s disability. Your doctor can help you locate support groups, organizations and counseling services in your community. Your child may also benefit from family support programs, school programs and counseling.

What is medulloblastoma

Medulloblastoma is an aggressive cancerous (malignant) brain tumor that only develops in the posterior fossa of the brain – classically in the midline of the cerebellum. The cerebellum is involved in muscle coordination, balance and movement. Medulloblastoma is an important tumor because medulloblastoma occurs in childhood and medulloblastoma can be very aggressive. Medulloblastoma is made up of small cells that are believed to have a neuro-ectodermal origin. Medulloblastoma is thought to arise from neural stem cell precursors in the granular cell layer of the cerebellum.

The brain is contained within the cranial vault, and is divided into several sections by folds of dura mater (one of the three membranes encasing the brain). The posterior fossa of the skull contains the cerebellum and brainstem.

The medulloblastoma is the second most common brain tumor in children. But the most common malignant (high grade) childhood brain tumor ¹⁾. Approximately 350 to 1,000 new cases are diagnosed in children and adults each year in the United States. Medulloblastoma accounts for 16-20% of all pediatric brain tumors, and 40-50% of all cerebellar tumors in childhood are medulloblastoma. In contrast, only 1% of brain tumors in adults are medulloblastomas. Medulloblastoma occurs bimodally, with 50% occur in the fist decade of life between 3 and 4 years and 8 and 9 years of age. The incidence of medulloblastoma peaked in those age 9 years and younger. Approximately 10 to 15% of medulloblastomas are diagnosed in infancy. Medulloblastoma accounts for less than 1% of central nervous system (CNS) tumors in adults, with highest incidence in adults 20 to 34 years of age. Medulloblastomas are slightly more common in males than in females. In 1 to 2% of patients, medulloblastoma is associated with Gorlin syndrome, a nevoid basal carcinoma syndrome. Medulloblastoma also occurs in up to 40% of patients with Turcot syndrome.

Incidence of medulloblastoma decreased with age ²⁾:

• Incidence was 0.53 per 100,000 population in children age-groups 0–4,
• 0.56 per 100,000 population in children age-groups 5–9,
• 0.33 per 100,000 population in children age-groups 10–14, and
• 0.16 per 100,000 population in adolescents age 15–19 years.

Based on different types of gene mutations, there are at least four subtypes of medulloblastoma. Though medulloblastoma is not inherited, syndromes such as Gorlin’s syndrome or Turcot’s syndrome might increase the risk of medulloblastoma.

The term Primitive Neuro Ectodermal Tumor or PNET is a relatively new term that is used to describe a group of tumors. In these Primitive Neuro Ectodermal Tumor (PNET), the type of cell seen is very similar. Their locations are quite different.

Tumors that fall under the heading Primitive Neuro Ectodermal Tumor (PNET) include:

• medulloblastoma (the most common),
• pineoblastoma,
• ependymoblastoma,
• retinoblastoma,
• neuroblastoma and
• esthesioneuroblastoma.

Other than the medulloblastoma, these are all rare tumors. These tumors generally occur in children.

Medulloblastomas initially grow into the cerebellum – the past of the brain that controls balance and posture. After this medulloblastoma may spread via the cerebrospinal fluid (CSF) into the spinal cord and other areas around the brain. As medulloblastoma grows it may block the flow of cerebrospinal fluid (CSF), leading to the development of hydrocephalus (increased head size caused by increased fluid in the brain) in young infants and children, or raised intracranial pressure in older children and adults. Medulloblastoma rarely spreads to other areas of the body.

The most common presenting symptoms of medulloblastoma cancer are headache, vomiting, and ataxia. Ataxia describes a lack of muscle control or coordination of voluntary movements, such as walking or picking up objects. Additional features that may be observed include lethargy, motor or cranial nerve impairment, gaze palsy, visual impairment due to hydrocephalia, vertigo/hearing loss, behavioral changes/irritability, and extracranial pain (e.g. back pain in those with spinal metastases). Around 30% of pediatric medulloblastoma cases present with metastases at diagnosis. Most metastases occur within the central nervous system by seeding via the cerebrospinal fluid (cranial or spinal), while spread to extracranial organs (e.g. bone marrow, liver, lungs) is very rare at diagnosis.

Children need to be seen at a center that has a team of pediatric specialists with expertise and experience in pediatric brain tumors, with access to the latest technology and treatments for children. Standard treatment includes surgery, chemotherapy, and, depending on the age of the patient, radiation therapy ³⁾.

Figure 1. Human brain

Figure 2. Medial aspect of the human brain

Figure 3. Cerebellum of brain

Figure 4. The Brainstem

Medulloblastomas classification

Successfully treating your child’s medulloblastoma depends largely on whether the tumor can be completely removed through surgery and whether the tumor has spread to other parts of the brain or spinal cord. Typically, post-surgery medulloblastomas are divided into three risk assessment groups:

• Infants (children under age 3)
• Standard risk (no evidence of disease with a complete removal of the tumor)
• High risk (evidence of incomplete removal or tumor spread elsewhere in the nervous system)

Medulloblastoma subtypes

Clinical researchers involved in international collaborations that have revealed that medulloblastomas are comprised of at least four different subtypes.

Medulloblastoma subtypes include ⁴⁾:

1. Wingless (WNT) Medulloblastoma
2. Sonic Hedgehog (SHH) Medulloblastoma
3. Group 3 (also called group C) Medulloblastoma
4. Group 4 (also called group D) Medulloblastoma

These groups are associated with specific age-groups, with SHH being most common in infants and adults, and all other groups being more common in childhood. Several review articles have elaborated on the details of these subgroups and their implications for diagnosis and treatment ⁵⁾.

Figure 5. Medulloblastoma

Figure 6. Medulloblastoma subtypes

Each of these subtypes has a different biological driver, and some subtypes require more intensive treatments than others. These findings are guiding clinical trials exploring new treatments for children with medulloblastoma.

After your doctors complete all necessary tests, they meet to review and discuss what they have learned about your child’s condition. Then your doctors will meet with you and your family to discuss the results and outline the best treatment options.

Medulloblastoma prognosis

The prognosis (chance of recovery) and treatment options depend on:

• the tumor’s molecular subtype (the specific genetic mutations within the tumor)
• the age of your child at the time of diagnosis
• the location of the tumor
• the amount of tumor remaining after surgery
• whether the cancer has spread to other parts of the central nervous system (brain and spinal cord), or to other parts of the body, such as the bones

The outcome for children with medulloblastoma has improved dramatically over the past several decades.

The outcomes in infants remain poor and many studies are underway to evaluate new treatment strategies in infants. Some include aggressive chemotherapy, including high-dose chemotherapy and stem cell transplant, and localized radiation therapy to minimize the harmful effects of radiation therapy on the developing brain.

Medulloblastoma survival rate

Provided the medulloblastoma is not widespread at diagnosis, it is often responsive to treatment, otherwise it is quite an aggressive tumor with a poor outcome. More than 73% of children survive longer than 5 years after diagnosis with 10-year survival was 64.7% for medulloblastoma ⁶⁾.

Survival rates are often used by doctors as a standard way of discussing a person’s prognosis (outlook). The 5-year survival rate refers to the percentage of children who live at least 5 years after their cancer is diagnosed. Of course, many children live much longer than 5 years (and many are cured).

To get 5-year survival rates, doctors have to look at children who were treated at least 5 years ago. Improvements in treatment since then might result in a better outlook for children now being diagnosed with brain tumors.

The numbers below come from the Central Brain Tumor Registry of the United States (CBTRUS) and are based on children aged 19 or younger who were treated between 2010 and 2014. There are some important points to note about these numbers ⁷⁾:

• In some cases, the numbers include a wide range of different types of tumors that can have different outlooks. For example, the survival rate for PNETs below includes medulloblastomas, pineoblastomas, and PNETs in other parts of the brain. Medulloblastomas tend to have a better outlook than the other PNETs. Therefore the actual survival rate for medulloblastomas would be expected to be higher than the number below, while the number for other PNETs would likely be lower.
• Medulloblastoma 5 year survival rate is about 73% (between 70.6-75.2 percent)
• Medulloblastoma 10 year survival rate is about 64.7% (between 61.8-67.4 percent)

Note that many other factors can also affect a child’s outlook, such as the location and extent of the tumor and how well it responds to treatment. Even taking these other factors into account, survival rates are at best rough estimates. Your child’s doctor knows your child’s situation and is your best source of information on this topic.

Medulloblastoma causes

The exact underlying cause of medulloblastoma is unknown. Most cases occur randomly for no apparent reason (sporadically). In some cases, medulloblastoma is associated with certain inherited diseases, including:

• Li-Fraumeni syndrome
• Nevoid basal cell carcinoma syndrome (Gorlin syndrome)
• Turcot syndrome

It’s important to understand that these and other brain tumors most often occur with no known cause. There’s nothing that you could have done or avoided doing that would have prevented the tumor from developing.

Many cases of medulloblastoma are associated with chromosomal abnormalities. These abnormalities are not inherited (i.e., are not passed on from one generation to the next), but occur at some unknown point during a child’s development, even during the development of a fetus or embryo. Although medulloblastomas are associated with chromosomal changes, they are not inherited.

In individuals with cancer, malignancies may develop due to abnormal changes in the structure and orientation of certain cells. As mentioned above, the specific cause or causes of such changes are unknown. However, research suggests that abnormalities of DNA (deoxyribonucleic acid), which is the carrier of the body’s genetic code, are the underlying basis of cellular malignant transformation. Depending upon the form of cancer present and several other factors, these abnormal genetic changes may occur spontaneously for unknown reasons (sporadically).

Evidence suggests that, in approximately one-third to one-half of individuals with a medulloblastoma, tumor cells may have a specific chromosomal abnormality, known as isochromosome 17q, with associated loss or inactivation of certain genetic information. Chromosomes, which are present in the nucleus of human cells, carry the genetic characteristics of each individual. Pairs of human chromosomes are numbered from 1 through 22, with an unequal 23rd pair of X and Y chromosomes for males and two X chromosomes for females. Each chromosome has a short arm designated as “p” a long arm identified by the letter “q” and a narrowed region at which the two arms are joined (centromere).

An isochromosome is an abnormal chromosome with identical arms on each side of the centromere. More specifically, in certain cases of medulloblastoma, there is duplication of the long arm and deletion of the short arm of chromosome 17. Some researchers suggest that such structural abnormalities of chromosome 17 may lead to inactivation of a gene on the chromosome that normally acts as a tumor suppressor, potentially leading to malignant transformation of certain cells. However, the implications of such findings remain unclear.

Additional chromosomal abnormalities have been identified in individuals with medulloblastoma including abnormalities on chromosome 1, 7, 8, 9, 10q, 11, and 16. How these various abnormalities play a role in the development of medulloblastoma is unknown. Further research is needed to determine the complex underlying mechanisms responsible for the development of a medulloblastoma.

In individuals with cancer, including medulloblastoma, malignancies may develop due to abnormal changes in the structure and orientation of certain cells known as oncogenes or tumor suppressor genes. Oncogenes control cell growth; tumor suppressor genes control cell division and ensure that cells die at the proper time. Oncogenes that are associated with medulloblastoma include ERBB2, MYCC, and OTX2. Many medulloblastomas are characterized by alterations in specific molecular signaling pathways that result in uncontrolled cell growth. Pathways implicated in medulloblastoma include the WNT pathway, the SHH pathway and the myc pathway.

In extremely rare cases, medulloblastomas occur in individuals who have certain inherited disorders including Gorlin syndrome (nevoid basal cell carcinoma), Turcot syndrome, Li Fraumeni syndrome, Rubinsten-Taybi syndrome, Nijmegen breakage syndrome, neurofibromatosis and ataxia-telangiectasia. Individuals with these disorders have an increased risk of developing a medulloblastoma.

Researchers theorize that medulloblastoma originates from immature cells that are somehow prevented from maturing (i.e., differentiating) into more specialized cells, which have “intended”, specific functions within the tissue in question. Such immature or incompletely differentiated cells may grow and divide at an unusually rapid, uncontrolled rate that cannot be contained by the body’s natural immune defenses. Eventually, such proliferation of abnormal cells may result in formation of a mass known as a tumor (neoplasm).

Several different subtypes of medulloblastoma have been identified including anaplastic (large cell) medulloblastoma; classic medulloblastoma; desmoplastic nodular medulloblastoma; medulloblastoma with extensive nodularity (MBEN); medullomyoblastoma; and melanotic medulloblastoma. The various subtypes of medulloblastoma appear different on a cellular level, but as yet to not influence treatment options. However, in the future such distinctions may be used to develop novel, targeted therapies based on a particular subtype and other factors.

Extensive transcriptional profiling of human medulloblastomas has recently yielded a second and more precise classification system that stratifies medulloblastomas according to their mRNA expression profiles. Four subgroups with distinct mRNA signatures have been identified, and are presently categorized as WNT, Sonic hedgehog (SHH), Group 3 and Group 4.

Medulloblastomas in the WNT subgroup feature genetic alterations that affect members of the Wnt signaling pathway, which are linked to the processes of embryogenesis and oncogenesis. Mutations of the ß-catenin gene and monosomy 6 are among the more common genetic events that define this subgroup, and the incidence rate among males and females is approximately equal. WNT subgroup medulloblastomas tend to affect older children and are rare in adults. Among the different subgroups, WNT tumors have the best prognosis and clinical outcomes. The SHH subgroup is characterized by up-regulation of members of the SHH signaling family. Common genetic events exclusive to this subgroup are mutations in the genes for PTCH, the receptor of SHH, and SUFU, a negative regulator of SHH signaling pathway. SHH tumors are the most common subgroup of medulloblastoma found in infants and adults, and they carry an intermediate prognosis. Like the WNT subgroup, the incidence of SHH tumors is equal for males and females. Group 3 tumors are characterized by over-amplification of MYC and genes related to phototransduction and glutamate signaling. These tumors are also known for their high frequency of metastasis and have the worst prognosis of any medulloblastoma subtype. Group 3 tumors are extremely rare in adults, and are more prevalent in males than females. The last subgroup, currently known as Group 4, is characterized by up-regulation of genes related to neuronal or glutameminergic signaling. Although these tumors are common across all age groups, comparatively little is known about them. Like Group 3, Group 4 tumors are more prevalent in males and have a high tendency to metastasize. Their prognosis is considered intermediate.

Medulloblastoma is sometimes classified as a primitive neuroectodermal tumor or PNET. PNETs are a group of tumors that arise from primitive nerve cells in the brain. A medulloblastoma is sometimes referred to as a primitive neuroectodermal tumor of the posterior fossa.

Risk factors for medulloblastoma

As for most brain tumors the cause of medulloblastoma is unknown. However, like all other brain tumors, there are a few known risk factors:

• Ionizing radiation is known to be a possible cause;
• Genetic studies show a familial risk

Cerebellar medulloblastoma is a feature of basal cell nevus syndrome, von Hippel-Lindau syndrome and familial adenomatous polyposis. In a formal risk analysis for brain tumors in familial adenomatous polyposis, Hamilton et al. ⁸⁾ found that the relative risk of cerebellar medulloblastoma in patients with familial adenomatous polyposis was 92 times that for the general population.

Medulloblastoma symptoms

The specific symptoms associated with a medulloblastoma will vary from one person to another based upon the exact location and size of a medulloblastoma and whether the tumor has spread to other areas. Affected individuals may not have all of the symptoms discussed below. Affected individuals should talk to their physician and medical team about their specific case, associated symptoms and overall prognosis.

Medulloblastomas typically involve the fluid-filled fourth cavity (ventricle) of the brain. The brain has four cavities called ventricles that are filled with cerebrospinal fluid (CSF) and joined by channels, through which CSF circulates. Because the tumor often fills the fourth ventricle, CSF circulation is obstructed, resulting in hydrocephalus. Hydrocephalus is a condition in which the accumulation of excess CSF in the brain causes a variety of symptoms, including repeated, often severe vomiting, lethargy and headaches that frequently occur in the morning and improve as the day goes on. Additional symptoms may include irritability, increased head size, and paralysis (paresis) of the muscles that help control eye movements (extraocular muscles).

Many infants and children with a medulloblastoma develop papilledema, a condition in which the optic nerve swells because of increased intracranial pressure. The optic nerve is the nerve that transmits impulses from the retina to the brain. Papilledema can cause reduced clarity of vision. Because many the symptoms associated with a medulloblastoma are nonspecific and often subtle, papilledema may the first sign that brings affected infants and children to the attention of a neurologist.

Children with medulloblastoma often have evidence of cerebellar dysfunction. Symptoms may include poor coordination, difficulty walking, and clumsiness (ataxia). Affected children may fall frequently and develop an unsteady, clumsy manner of walking (unsteady gait). They may tend to stand with their feet widely separated, stagger or sway when walking and easily lose their balance.

As a tumor grows or spreads, additional symptoms can develop. Such symptoms may include double vision (diplopia), rapid, jerky movements of the eyes (nystagmus), facial weakness, ringing in the ears (tinnitus), hearing loss and a stiff neck. Some children with double vision may tilt their heads in an effort align the two images.

Signs and symptoms of medulloblastoma may include:

• Nighttime or morning headache (generally upon awakening in the morning)
• Poor coordination and unsteady walk (ataxia)
• Nausea and vomiting
• Dizziness
• Double vision (diplopia)
• Head bobbing or neck tilt
• Nystagmus (an abnormal, side-to-side movement of the eyes)
• Lethargy (tiredness) or confusion
• Hydrocephalus due to obstruction of normal cerebrospinal fluid circulation
• Changes in personality or behavior
• Seizures

Rarely, medulloblastoma can spread into the central nervous system or the spinal canal, and your child may experience:

• loss of strength in the lower extremities
• back pain
• bowel and bladder control issues
• difficulty walking

These symptoms may be related to the tumor itself or be due to the buildup of pressure within the brain.

Medulloblastoma diagnosis

Your doctor may start with a neurological exam of your child.

Tests and procedures used to diagnose medulloblastoma include:

• Neurological exam. During this procedure, vision, hearing, balance, coordination and reflexes are tested. This helps determine which part of the brain might be affected by the tumor.
• Imaging tests. Imaging tests can help determine the location and size of the brain tumor. These tests are also very important to identify pressure or blockage of the CSF pathways. A computerized tomography (CT) scan or magnetic resonance imaging (MRI) may be done right away. These tests are often used to diagnose brain tumors. Advanced techniques, such as perfusion MRI and magnetic resonance spectroscopy, also may be used.
• Tissue sample testing (biopsy). A biopsy is usually not done, but it may be recommended if the imaging tests are not typical of medulloblastoma. The sample of suspicious tissue is analyzed in a lab to determine the types of cells.
• Removal of cerebrospinal fluid for testing (lumbar puncture). Also called a spinal tap, this procedure involves inserting a needle between two bones in the lower spine to draw out cerebrospinal fluid from around the spinal cord. The fluid is tested to look for tumor cells or other abnormalities. This test is only done after managing the pressure in the brain or removing the tumor.

A medulloblastoma may appear similar to other kinds of brain tumors. After surgery, a pathologist can examine the tumor cells under a microscope and make a definitive diagnosis. Once the diagnosis of medulloblastoma is clear, your doctors can determine the most appropriate treatment for your child.

To see if the medulloblastoma has spread, the doctor may recommend a lumbar puncture to test your child’s cerebrospinal fluid for cancer cells.

Medulloblastoma treatment

The treatment for medulloblastoma depends on a number of factors including the general health of the patient and the size and position of the tumor. Treatment for medulloblastoma usually includes surgery followed by radiation or chemotherapy, or both.

Your child’s physician will determine a specific course of medulloblastoma treatment based on several factors, including:

• your child’s age, overall health and medical history
• type, location, and size of the tumor
• extent of the disease
• your child’s tolerance for specific medications, procedures or therapies
• how your child’s doctors expects the medulloblastoma cancer to behave

Medulloblastomas occur much more commonly in children than adults, and treatment is not without risk. There may be some long-term effects of treatment including growth and hormonal changes, behavioral changes and possible learning problems, and these need to be discussed with the treating doctor.

Treatment for medulloblastoma focuses on removing as much of the tumor as safely possible and relieving pressure in the child’s skull (intracranial pressure) due to swelling or hydrocephalus. In addition to surgical removal of the tumor, the doctor may sometimes recommend a shunt to help drain cerebrospinal fluid buildup and steroid treatments to reduce tumor swelling.

Surgery is followed by radiation and chemotherapy. These therapies address cancer cells that might have been unreachable by surgery and those that have spread from the tumor to other parts of the brain or spinal cord. Medulloblastoma spread and recurrence is common; radiation and chemotherapy can reduce the risks.

This three-part approach – surgery, radiation and chemotherapy – can offer survival in up to 75 percent of patients. It is important to understand that each of the three treatments, especially radiation treatment of the brain, may cause complications that could affect your child’s development.

It is essential to discuss each stage of your child’s therapy thoroughly with your doctors so you can make informed choices for your child and understand potential benefits and risks.

Enrolling your child in a clinical trial may offer additional options for treatment. Your doctor can refer you to studies if they are appropriate.

• Surgery to relieve fluid buildup in the brain. A medulloblastoma may grow to block the flow of cerebrospinal fluid, which can cause a buildup of fluid that puts pressure on the brain (hydrocephalus). Surgery to create a pathway for the fluid to flow out of the brain (external ventricular drain or ventriculoperitoneal shunt) may be recommended. Sometimes this procedure can be combined with surgery to remove the tumor.
• Endoscopic third ventriculostomy (ETV) or ventriculo-peritoneal shunt (VP shunt): In an endoscopic third ventriculostomy, surgeons create a small hole that allows fluid to flow around the blockage and into the spinal column. About 90 percent of children with symptoms of hydrocephalus will undergo this procedure. In some cases, children may have an alternative procedure in which a tube is installed to drain excess fluid into the abdomen (VP shunt).
• Surgery to remove the medulloblastoma. A pediatric or adult brain surgeon (neurosurgeon) removes the tumor, taking care not to harm nearby tissue. But sometimes it’s not possible to remove the tumor entirely because medulloblastoma forms near critical structures deep within the brain. All patients with medulloblastoma should receive additional treatments after surgery to target any remaining cells.
• Radiation therapy. You might have radiotherapy to the brain and sometimes the whole of the spinal cord. About 1 in 5 people (20%) with meduloblastoma have spread to the spinal cord when they are diagnosed. In other people, there is a risk that it will spread. So you have radiotherapy to reduce this risk or treat spread that is already there. A pediatric or adult radiation oncologist administers radiation therapy to the brain and spinal cord using high-energy beams, such as X-rays or protons, to kill cancer cells. Standard radiation therapy can be used, but proton beam therapy — available at a limited number of major health care centers in the United States — delivers higher targeted doses of radiation to brain tumors, minimizing radiation exposure to nearby healthy tissue.
• Chemotherapy. Chemotherapy uses drugs to kill tumor cells. Typically, children and adults with medulloblastoma receive these drugs as an injection into the vein (intravenous chemotherapy). Chemotherapy may be recommended after surgery or radiation therapy, or in certain cases, at the same time as radiation therapy. In some cases, high dose chemotherapy followed by stem cell rescue (a stem cell transplant using the patient’s own stem cells) may be used.
• Clinical trials. Clinical trials enroll eligible participants to study the effectiveness of new treatments or to study new ways of using existing treatments, such as different combinations or timing of radiation therapy and chemotherapy. These studies provide a chance to try the latest treatment options, though the risk of side effects may not be known. Talk with your doctor for advice.

Posterior fossa syndrome

About 25 out of 100 (25%) people have particular symptoms after medulloblastoma surgery. The symptoms are called posterior fossa syndrome and they can be very mild or severe. Symptoms include difficulty talking, swallowing or walking. This syndrome is thought to be more unusual in children.

“Posterior fossa mutism” is a condition that may occur after surgery. Within 24 hours, the child develops an inability to speak, has problems with balance and has difficulty with swallowing. The condition may range from mild to severe. The cause of this condition is not entirely known but it is unique to this area of the brain.

Posterior fossa syndrome might develop from one day to a week after medulloblastoma surgery. The symptoms usually improve slowly over a few weeks or months. But they may not go away completely in some people. Research is trying to find out what causes posterior fossa syndrome.

Complications of treatment

Other complications include post-operative infection, paralysis, nerve palsies, cognitive dysfunction and growth retardation.

Treatment for children under 3

The specialist will usually avoid using radiotherapy to the whole brain and spine if your child is younger than 3. Their young age makes them more likely to develop long term side effects.

The specialist might recommend chemotherapy instead. This aims to keep your child’s tumor under control until radiotherapy is likely to cause less damage.

In general your child is likely to have high dose chemotherapy with a number of drugs. They might also have radiotherapy just to the area containing the tumor. This way, radiotherapy to the whole brain and spinal cord can be delayed until your child is older. Or it might be avoided altogether.

Your child has chemotherapy using a number of drugs given into their vein. They also have chemotherapy into the fluid around the spinal cord (intrathecal chemotherapy).

Follow up

You will have regular check ups once you finish your treatment. Your doctor will examine you and ask about your general health.

This is your chance to ask questions and to tell your doctor if anything is worrying you.

How often you have check ups depends on your individual situation.

Coping and support

Finding out you or your child has a brain tumor may feel overwhelmed, as though things are out of your control, just when you need to make crucial decisions. Coping with the shock, fear and sadness that come with a cancer diagnosis can take time. With time, each person finds a way of coping and coming to terms with the diagnosis.

You are likely to have a range of emotions that change very quickly. You might feel upset, frightened and confused. One day you might feel positive and able to cope but the next day feel the exact opposite. This is natural.

Counseling can help you to cope with the difficulties you’ll face. It can help to reduce your stress and improve your quality of life.

You are more able to cope and make decisions if you have information about your brain tumor and its treatment. Information also helps you to know what to expect.

Taking in information can be difficult at first. Make a list of questions before you see your doctor. Take someone with you to remind you what you want to ask and help remember the answers.

Ask your doctors and nurses to explain things again if you need them to.

Remember, you don’t have to sort everything out at once. It might take some time to deal with each issue. Ask for help if you need it.

Treatment causes side effects. These can be mild or more severe. Tell your doctor or nurse if you have any or if they get worse. They can treat them and help you find ways of coping.

What questions should I ask if my child has medulloblastoma?

You and your family are key players in your child’s medical care. It’s important that you share your observations and ideas with your child’s health care provider and that you understand your doctor’s recommendations. If your child has been diagnosed with medulloblastoma, you probably have a lot on your mind. So it’s often helpful to write questions down. Some of the questions you may want to ask include:

• What does a diagnosis of medulloblastoma mean for my child?
• How will you manage my child’s symptoms?
• What are my child’s treatment options?
• How many other children with medulloblastoma does your team treat each year?
• What are the possible short and long-term complications of treatment?
• What is the long-term outlook for my child?
• How likely is it that the tumor will come back?
• What services are available to help my child and my family cope?

Until you find what brings you the most comfort, consider trying to:

• Find out enough about the cancer to make decisions about your care. Ask your doctor for the specifics about your cancer, such as its type and stage. And ask for recommended sources of information where you can learn more about your treatment options. The National Cancer Institute ⁹⁾ and the American Cancer Society ¹⁰⁾ are good places to start.
• Stay connected to friends and family. Your friends and family can provide a crucial support network for you during your cancer treatment. As you begin telling people about your cancer diagnosis, you’ll likely get offers for help. Think ahead about things you may like help with, whether it’s having someone to talk to if you’re feeling low or getting help preparing meals.
• Find someone to talk to. You might have a close friend or family member who’s a good listener. Or talk to a counselor, medical social worker, or pastoral or religious counselor.

Consider joining a support group for people with cancer. You may find strength and encouragement in being with people who are facing the same challenges you are. Ask your doctor, nurse or social worker about groups in your area. Or try online message boards, such as those available through the American Cancer Society ¹¹⁾.

Talking to other people

Talking to your friends and relatives about your brain tumor can help and support you. But some people are scared of the emotions this could bring up and won’t want to talk. They might worry that you won’t be able to cope with your situation.

It can strain relationships if your family or friends don’t want to talk. But talking can help increase trust and support between you.

Help your family and friends by letting them know if you would like to talk about what’s happening and how you feel.

You might find it easier to talk to someone outside your own friends and family. For example your specialist nurse, or other people in a similar situation to you. You could join a support group, or contact one of the brain tumor charities.

What is Lennox Gastaut syndrome

Lennox-Gastaut syndrome is a severe form of epilepsy characterized by recurrent seizures (epilepsy) that begin in infancy or early childhood, usually between ages 3 and 5 ¹⁾. Affected individuals have multiple types of seizures that vary among individuals, a particular pattern of brain activity called slow spike-and-wave measured by a test called an electroencephalogram (EEG), and impaired mental abilities.

Lennox‐Gastaut syndrome is an age‐specific epileptic encephalopathy, characterized by epileptic seizures, slow spike‐waves in the waking electroencephalogram (EEG) and fast rhythmic bursts during sleep, psychomotor delay and personality disorders ²⁾.

Lennox-Gastaut syndrome affects an estimated 1 to 2 per million people. Lennox-Gastaut syndrome accounts for less than 5 percent of all cases of childhood epilepsy. For unknown reasons, Lennox-Gastaut syndrome affects males slightly more often than females.

The following seizure types and EEG findings are associated with Lennox Gastaut syndrome ³⁾:

• Tonic seizures (stiffening of the body, upward eye gaze, dilated pupils, and altered breathing patterns)
• Atypical absences (staring spells)
• Atonic seizures (brief loss of muscle tone, which could cause abrupt falls)
• Myoclonic seizures (sudden muscle jerks), and
• Generalized tonic-clonic seizures (muscle stiffness and rhythmic jerking).

1. Tonic axial seizures

These are the hallmark seizure type, and may be axial, appendicular or global, symmetrical, or unilateral. They consist of flexion of the neck and body, extension of the arms and legs, and contraction of the facial muscles. There may be associated apnoea, eye rolling and facial flushing. Consciousness is usually impaired. They are diurnal and nocturnal. They are usually brief, lasting seconds. The EEG shows discharges of fast bilateral bursts, particularly seen during sleep, predominately anteriorly or on the vertex.

2. Atypical absence seizures

These occur in the majority of cases and are frequently subtle. Loss of consciousness may be incomplete, allowing the individual to continue ongoing activities. However they are often accompanied by loss of muscle tone, myoclonic jerks and drooling ⁴⁾. EEG shows irregular diffuse slow spike‐wave activity at 2 to 2.5 Hz.

3. Atonic seizures

These are less frequent than the tonic axial seizures. They are manifested by a rapid loss of tone that may involve a sudden head drop or fall to the ground and are associated with polyspikes and slow waves, or diffuse spike waves on the EEG ⁵⁾.

4. Myoclonic seizures

These are considered rare and in children with prominent myoclonic jerks alternative diagnoses such as myoclonic astatic epilepsy or Dravet’s syndrome should be considered. Rarely they may precede atonic attacks as myoclonic‐atonic attacks. They can be associated with slow waves, polyspike waves, diffuse rapid spike waves or brief discharges predominantly in the anterior regions.

5. Tonic‐clonic and partial‐onset seizures

These are less commonly seen in Lennox Gastaut syndrome than other epilepsies, but may nonetheless be present in a minority of cases.

6. Status epilepticus and non‐convulsive status

Occurs in approximately two‐thirds of patients and usually consists of continuous absence seizures punctuated by recurring tonic seizures; may be difficult to recognize.

EEG (electroencephalogram)

This is abnormal in the vast majority of cases showing 2‐ to 2.5‐Hz slow spike‐wave discharges over both hemispheres with multifocal spikes and spike waves predominating in the frontal and temporal areas. In addition, the presence of fast (10 Hz) rhythms associated with tonic attacks or sometimes with minimal or no clinical manifestations, mainly during non‐REM sleep, is considered a necessary criteria by some authors. However, in some people the characteristic EEG abnormalities may be variable and even transient.

In Lennox-Gastaut syndrome, the most common seizure type is tonic seizures, which cause the muscles to stiffen (contract) uncontrollably. These seizures typically occur during sleep; they may also occur during wakefulness and cause sudden falls. Also common are atypical absence seizures, which cause a very brief partial or complete loss of consciousness. Additionally, many affected individuals have episodes called drop attacks, which cause sudden falls that can result in serious or life-threatening injuries. Drop attacks may be caused by sudden loss of muscle tone (described as atonic) or by abnormal muscle contraction (described as tonic). Other types of seizures have been reported less frequently in people with Lennox-Gastaut syndrome. Seizures associated with Lennox-Gastaut syndrome often do not respond well to therapy with anti-epileptic medications.

Although each seizure episode associated with Lennox-Gastaut syndrome is usually brief, more than two-thirds of affected individuals experience prolonged periods of seizure activity (known as status epilepticus) or episodes of many seizures that occur in a cluster.

Most children with Lennox-Gastaut syndrome have intellectual disability or learning problems even before seizures begin. These problems may worsen over time, particularly if seizures are very frequent or severe. Some affected children develop additional neurological abnormalities and behavioral problems. Many also have delayed development of motor skills such as sitting and crawling. As a result of their seizures and intellectual disability, most people with Lennox-Gastaut syndrome require help with the usual activities of daily living. However, a small percentage of affected adults live independently.

People with Lennox-Gastaut syndrome have a higher risk of death than their peers of the same age. Although the increased risk is not fully understood, it is partly due to poorly controlled seizures and injuries from falls.

Lennox-Gastaut syndrome can be caused by a variety of conditions, including brain malformations, tuberous sclerosis, perinatal asphyxia, severe head injury, central nervous system infection, and inherited genetic and inherited degenerative or metabolic conditions. In 30-35 percent of individuals, no cause can be found.

Generally, three findings are necessary for the diagnosis: multiple generalized seizure types; a slow spike-and-wave pattern (less than 2.5 Hz) on electroencephalogram (EEG); and cognitive dysfunction ⁶⁾. The International League Against Epilepsy Task Force most recently classified the disorder as an epileptic encephalopathy. Epileptic encephalopathies are a group of disorders in which seizure activity leads to progressive cognitive dysfunction.

Lennox-Gastaut syndrome can be very difficult to treat. A combination of seizure medications and other treatments may be used to improve seizure control and other associated conditions.

Other treatment options include dietary therapy with the ketogenic diet, vagus nerve stimulation, and epilepsy surgery (typically a corpus callostomy, which involves severing the band of nerve fibers that connect the two halves of the brain to prevent seizures from spreading). Medication may be combined with the other treatments to optimize seizure control. Children who improve initially may later show tolerance to a drug or have uncontrollable seizures.

How will the seizures in Lennox Gastaut syndrome keep changing?

Characteristics of Lennox Gastaut syndrome are likely to change in the adult years. As the patient reaches their 20s, only 30-50% maintain the characteristic EEG (slow spike-wave pattern) and clinical characteristics ⁷⁾. In 33% of patients with cryptogenic Lennox Gastaut syndrome (no underlying cause) and 55% with symptomatic Lennox Gastaut syndrome (known cause), the characteristic Lennox Gastaut syndrome features disappeared with age ⁸⁾. Seizure types often change or decrease in frequency, while behavior disturbances may persist or change with age.

Lennox Gastaut syndrome prognosis

The prognosis for individuals with Lennox-Gastaut syndrome varies. There is no cure for the disorder. Complete recovery, including freedom from seizures and normal development, is very rare.

Psychomotor delay and neuropsychiatric symptoms occur in 90% of people with Lennox Gastaut syndrome. Some children have delayed development prior to the onset of their seizures as part of a predisposing condition, for example West’s syndrome (infantile spasms). Nevertheless even in these individuals further regression of development is often seen after the onset of Lennox Gastaut syndrome. Language is frequently affected, with both slowness in ideation and expression in addition to difficulties of motor dysfunction. Severe behavioural disorders are nearly always present. There is also a tendency for psychosis to develop with time. The long‐term prognosis is poor; although the epilepsy often improves, complete seizure freedom is rare and conversely the mental and psychiatric disorders tend to worsen with time ⁹⁾.

Lennox Gastaut syndrome life expectancy

The mortality rate associated with Lennox-Gastaut Syndrome ranges from 3 to 7%, with many deaths related to accidents ¹⁰⁾. People with Lennox- Gastaut Syndrome have an increased risk of death compared to their peers of the same age. Although the increased risk is not fully understood, it is partly due to poorly controlled seizures and injuries from falls ¹¹⁾.

Lennox Gastaut syndrome symptoms

The symptoms of Lennox-Gastaut syndrome usually begin during infancy or childhood, most often between 3 to 5 years of age. Multiple types of seizures, which are basically electrical disturbances in the brain, affect children with Lennox-Gastaut syndrome. Most affected individuals experience multiple types of seizures, multiple times throughout the day. As affected individuals grow older, the types and frequency of seizure activity may change.

The most common types of seizures associated with Lennox-Gastaut syndrome are tonic and atonic seizures. Tonic seizures cause increased muscle tone and muscle stiffness. They are characterized by sustained muscle contractions that can cause mild abnormalities such as a slight bend of the body and brief interruption of breathing or more significant problems such as muscle spasms of the face and flexion or extension of the arms and legs. Affected children may extend their arms over their heads similar to a ballet dancer. Tonic seizures are usually brief (lasting between a few seconds and a minute) and are especially prevalent at night during sleep, but can also occur during the day. There is usually a brief loss of consciousness during a tonic seizure. Tonic seizures that occur when awake can cause affected individuals to fall.

Atonic seizures cause a sudden loss of muscle tone and limpness. They can cause the head to drop or nod, problems with posture or sudden falls. Atonic seizures are also known as drop attacks. Atonic seizures can lead to injuries of the head and face because of sudden, unexpected falls. When sitting, affected individuals may collapsed forward or backward at the waist. Atonic seizures may only partially affect consciousness and usually last only a few seconds.

A third type of seizure commonly associated with Lennox-Gastaut syndrome is atypical absence seizures. This type of seizure is associated with a period of unconsciousness usually marked by unresponsive staring. Absence seizures usually begin and end abruptly and the affected individual usually resumes activity with no memory of the episode. Absence seizures do not cause convulsions and may be so mild that they go unnoticed. They usually last only a couple to several seconds. If the child is developmentally delayed, the parents may only notice a subtle change in function or responsiveness.

Additional types of seizures can affect individuals with Lennox-Gastaut syndrome less often. These include myoclonic seizures, which are characterized by abnormal, jerky movements and may occur alone or in conjunction with atypical absence seizures; tonic-clonic seizures (once known as grand mal seizures), which last a couple of minutes and are characterized by stiffening of the limbs and then jerking of the limbs and face; and partial seizures, which involve electrical abnormalities in a limited area of the brain and come in a variety of forms. Some individuals with Lennox-Gastaut syndrome experience prolonged, uninterrupted seizure activity that lasts for more than 30 minutes (nonconvulsive status epilepticus). Nonconvulsive status epilepticus may be associated with a child being unaware or inattentive and, in some cases, may be so subtle that is goes unnoticed. Nonconvulsive status epilepticus requires medical intervention.

Intelligence is usually, but not always, affected in children with Lennox-Gastaut syndrome. Affected children may experience varying degrees of cognitive dysfunction and delays in reaching developmental milestones such as sitting, crawling or walking. Children with Lennox-Gastaut syndrome may develop normally before the onset of seizures, and then lose previously acquired skills (psychomotor regression).Because the seizures associated with Lennox-Gastaut syndrome are usually resistant to treatment, intellectual impairment and learning problems may worsen over time. Children with Lennox-Gastaut syndrome may also develop behavioral problems ranging from hyperactivity and irritability to autistic symptoms and psychosis.

In some cases, individuals with Lennox-Gastaut syndrome may have been initially affected by infantile spasms. Infantile spasms, which are also known as West syndrome, are characterized by sudden, involuntary contractions of the head, neck, and trunk and/or uncontrolled extension of the legs and/or arms.

Lennox Gastaut syndrome causes

Lennox-Gastaut syndrome can have many different causes. Lennox-Gastaut syndrome likely has a genetic component, although the specific genetic factors are not well understood.

In approximately 70-80 percent of patients, Lennox-Gastaut syndrome has an identifiable cause. Most cases of Lennox-Gastaut syndrome are caused by an existing neurological abnormality. These cases may be referred to as symptomatic Lennox-Gastaut syndrome, can be associated with brain injuries that occur before or during birth, reduced oxygen supply that occurs before birth (perinatal hypoxia), problems with blood flow in the developing brain, stroke, brain infections such as encephalitis or meningitis, or other disorders affecting the nervous system. Lennox-Gastaut syndrome can also result from brain malformations such as forms of cortical dysplasia, which are abnormalities in the outer surface of the brain (cerebral cortex). Many people with Lennox-Gastaut syndrome have a history of epilepsy beginning in infancy (infantile spasms) or a related condition called West syndrome before developing the features of Lennox-Gastaut syndrome.

In addition, mutations in several genes have been associated with Lennox-Gastaut syndrome, each in a small number of affected individuals. These genes are involved in the function of nerve cells in the brain, but it is unclear how changes in them contribute to the development of Lennox-Gastaut syndrome. The condition can also occur as part of a genetic disorder such as tuberous sclerosis complex.

Approximately 17-30 percent of individuals with Lennox-Gastaut syndrome have a previous history of West syndrome. In general, these cases tend to be more severe.

In about 10 percent of affected individuals, Lennox-Gastaut syndrome may also be classified as cryptogenic, in which the cause is unknown or cannot be determined after evaluation. These individuals have no history of seizures, neurological problems, or delayed development. Cryptogenic cases are presumed to result from an unidentified condition (secondary Lennox-Gastaut syndrome). Individuals with cryptogenic Lennox-Gastaut syndrome do not have a previous history of seizure activity, prior neurological problems or cognitive impairment before the development of the disorder. Cryptogenic cases generally have a later onset than symptomatic cases.

In some cases of Lennox-Gastaut syndrome no associated condition is present or presumed and the cause of the disorder is unknown.

Although the cause of Lennox-Gastaut is known in most cases, the exact underlying mechanisms that ultimately bring about the various seizures that characterize the disorder are unknown. Researchers have not discovered any genes that are associated with Lennox-Gastaut syndrome, although the disorder may have a genetic component that contributes to its development. More research is necessary to determine the specific factors, including any potential genetic factors that are involved in the development of Lennox-Gastaut syndrome.

Lennox Gastaut syndrome inheritance pattern

Most cases of Lennox-Gastaut syndrome are sporadic, which means they occur in people with no history of the disorder in their family. When Lennox-Gastaut syndrome is associated with a genetic change, the mutation is usually not inherited but occurs as a random (de novo) event during the formation of reproductive cells (eggs or sperm) in an affected person’s parent or in early embryonic development. However, 3 to 30 percent of people with this condition have a family history of some type of epilepsy, indicating that inherited genetic factors may play a role in some cases of Lennox-Gastaut syndrome.

Lennox Gastaut syndrome diagnosis

Lennox-Gastaut syndrome is defined as having a clinical triad that must be identified for a diagnosis. This triad consists of multiple seizures of different types, a distinctive EEG brain wave pattern (slow [1.5- to 2.5-Hz] spike-and-wave pattern) and some degree of cognitive impairment and behavioral abnormalities. However, these symptoms may not all be present at the onset of the disorder, making an accurate diagnosis of Lennox-Gastaut syndrome difficult. The wide variety of potential causes of Lennox-Gastaut syndrome also complicates the diagnosis.

A diagnosis of Lennox-Gastaut syndrome is usually made based upon a thorough clinical evaluation, a detailed patient history and a complete physical and neurological evaluation including advanced imaging techniques, such as electroencephalography (EEG) and magnetic resonance imaging (MRI). During an EEG, the brain’s electrical impulses are recorded. In individuals with Lennox-Gastaut syndrome, such EEG testing typically reveals the distinctive brain wave pattern (slow [1.5- to 2.5-Hz] spike-and-wave pattern). During a MRI scan, three-dimensional images are produced that reflect the brain’s anatomy; such scanning helps physicians examine brain structure and potentially locate the cause of the seizure activity.

Lennox Gastaut syndrome treatment

Lennox-Gastaut syndrome can be very difficult to treat. A combination of seizure medications and other treatments may be used to improve seizure control and other associated conditions. However, no specific therapy for Lennox-Gastaut syndrome is effective in all cases and the disorder has proven particularly resistant to most therapeutic options. The three main forms of treatment of Lennox-Gastaut syndrome are anti-epileptic drugs, dietary therapy (typically the ketogenic diet) or device/surgery (vagus nerve stimulation therapy or corpus callosotomy). Rarely, resective surgery is an option.

Treatment may require the coordinated efforts of a team of specialists. Pediatricians, neurologists, pediatric neurologists, surgeons, and/or other healthcare professionals may need to systematically and comprehensively plan an affected child’s treatment. Families need to work with healthcare professionals to develop a treatment plan that covers various potential situations such as seizure emergencies, routine medical illnesses, or what to do if an affected individual misses a dosage of medication. Families should also keep a list of which medications can possibly worsen Lennox-Gastaut syndrome. An affected individual’s treatment regimen will need repeated revisions throughout a person’s life as the types and frequency of seizures may change and the effectiveness of a particular therapy can lessen. Other healthcare providers are frequently consulted, including social workers, neuropsychologists, psychiatrists and rehabilitation services (occupational, physical and speech therapy).

Anti-epileptic drugs are usually given to individuals with Lennox-Gastaut syndrome, but the individual response is highly variable. In some cases, it is possible that treatment with anti-epileptic drugs may help reduce or control various types of seizure activity associated with Lennox Gastaut syndrome. The medication valproate is generally considered a first-line therapy for various seizure types. However, because individuals with Lennox-Gastaut syndrome have different types of seizures, they often require therapy with multiple types of anti-epileptic drugs. Such medications may include clobazam, clonazepam, felbamate (closely monitored), lamotrigine, rufinamide, topiramate, and cannabidiol. However, the optimum treatment for Lennox Gastaut syndrome remains uncertain and no study to date has shown any one drug to be highly efficacious; rufinamide, lamotrigine, topiramate and felbamate may be helpful as add‐on therapy, clobazam may be helpful for drop seizures. Until further research has been undertaken, clinicians will need to continue to consider each patient individually, taking into account the potential benefit of each therapy weighed against the risk of adverse effects ¹²⁾. In addition, anti-epileptic drugs may be associated with significant side effects, especially in individuals who receive multidrug, high-dose regimens. anti-epileptic drugs can also become less effective over time. Being on multiple medications, which may cause sedation, can sometimes worsen seizure control.

Valproate (valproic acid) is generally considered the first-line therapy for Lennox-Gastaut syndrome because it is effective against a wide spectrum of seizures. Valproate is usually first given alone (monotherapy) and if ineffective another drug such as lamotrigine, topiramate, rufinamide or clobazam may be added.

A variety of specific drugs have been approved by the Food and Drug Administration (FDA) for the treatment of Lennox-Gastaut syndrome including topiramate (Topamax). Topiramate has been approved as an add-on (adjunctive) therapy for children and adults. The drug is manufactured by Ortho-McNeil Neurologics.

The FDA has also approved the anticonvulsant drug felbamate (Felbatol) for the treatment of seizures in children with Lennox-Gastaut syndrome. Due to the occurrence of rare but serious side effects from the drug, physicians should become familiar with the medication and know how to monitor for side-effects before prescribing the medication. This drug, while effective, is not typically first or second line because of the side-effect concerns.

In addition, the FDA has approved the lamotrigine (Lamictal) as an add-on (adjunctive) therapy (i.e., as a medication to be used in association with other appropriate anticonvulsant medications) for the treatment of generalized seizures associated with Lennox-Gastaut syndrome.

In 2008, the FDA approved rufinamide (Banzel) for the use as an adjunctive (add-on) treatment for seizures associated with Lennox-Gastaut syndrome. Rufinamide decreases seizure frequency in some individuals and seems to be particularly effective for atonic or drop attack seizures.

Clobazam (Onfi) was approved by the FDA in 2011 to treat the seizures associated with Lennox-Gastaut syndrome.

In June 2018 the U.S. Food and Drug Administration approved cannabidiol (Epidolex, derived from marijuana) for the treatment of seizures associated with Lennox-Gastaut syndrome in individuals ages 2 and older. The drug contains only small amount of the psychoactive element in marijuana and does not induce euphoria associated with the drug.

Additional therapies that have been used to treat individuals with Lennox-Gastaut syndrome include the ketogenic diet, Vagus nerve stimulation Therapy and various surgical techniques. These options are generally reserved for individuals who do not respond to or no longer respond to drug therapy, and are typically combined with drug therapy (The exception is dietary therapy, which is typically added to drug therapy, but rarely maybe successful by itself in this population.).

The ketogenic diet may reduce seizure activity in some individuals with Lennox-Gastaut syndrome. The ketogenic diet is a high fat, low carbohydrate diet that makes the body burn fat for energy instead of sugar (glucose). It is a strict diet that requires rigid compliance and commitment. The ketogenic diet can have side effects and individuals following the diet should be routinely monitored by their physicians and a trained nutritionist. The effectiveness of the ketogenic diet varies from one individual to another. Researchers do not understand why the diet is effective in treating seizures or why it is effective for some people, but not others.

Some individuals with Lennox-Gastaut syndrome, especially those who have not responded to other forms of therapy, may be treated with surgical therapies including complete corpus callosotomy or vagus nerve stimulation.

A corpus callosotomy is a surgical procedure in which the cerebral hemispheres are disconnected by cutting the corpus callosum, which is a large bundle of nerves that connects the two halves (hemispheres) of the brain and allows them to share information. This procedure does not include the cutting of brain tissue. This procedure is generally reserved for individuals who suffer from intractable seizures that lead to injuries (e.g., drop seizures or frequent generalized tonic-clonic seizures) or are potentially life-threatening. It is most effective for atonic, tonic and tonic-clonic seizures.

Vagus nerve stimulation is a procedure in which a device called a pulse generator is inserted into the chest and a wire is run underneath the skin to the vagus nerve in the neck. The pulse generator is similar to a pacemaker and transmits mild, electrical impulses to the brain via the vagus nerve. These impulses prevent seizures from occurring. The intensity and timing of the nerve impulses are determined based upon each individual’s needs. This is combined with drug therapy and most effective for drop seizures and generalized tonic-clonic seizures.

What is infantile spasms

Infantile spasms often called West Syndrome, are a rare special type of seizure with both focal and generalized features. Infantile spasms onset is usually in the first year of life (over 90% of cases begin before 12 months of life), typically often begin between three and six months of age but some children may experience spasms as early as one month and appear as brief stiffening movements lasting one to two seconds each. The seizures often look like a sudden bending forward of the body with stiffening of the arms and legs lasting for 1-2 seconds; some children arch their backs as they extend their arms and legs. Infantile spasms can involve the whole body or only the head or a part of the face. Spasms typically repeat every few seconds in what is called a cluster, and the infant usually appears to recover or relax between each spasm. Clusters of spasms often occur after waking from sleep and often occur in multiple clusters and hundreds of seizures per day.

Infantile spasms is characterized by epileptic spasms, which consist of massive myoclonic jerks of the body, which can be extensor or flexor (or both) in nature. Infantile spasms often are accompanied by developmental problems and a characteristic interictal brain wave pattern on electroencephalography (EEG) testing called hypsarrhythmia. Most children, but not all, will have EEG readings of hypsarrhythmia. When all three features are present, the term “West syndrome” is commonly used. West syndrome is characterized by an electroclinical triad of (1) epileptic spasms, (2) hypsarrhythmia on EEG study, and (3) developmental stagnation or regression. West syndrome is considered to be catastrophic because of the frequent sequelae of global neurodevelopmental delay, significant intellectual disability, and medically refractory epilepsy.

Infantile spasms (West syndrome) usually stop by age five, but may be replaced by other seizure types. Many underlying disorders, such as birth injury, metabolic disorders, and genetic disorders can give rise to infantile spasms, making it important to identify the underlying cause. In some children, no cause can be found.

The incidence of infantile spasms is 2 to 3 per 10,000 live births ¹⁾, with a lifetime prevalence of 1.5 to 2 per 10,000 children ²⁾. About 1,200 children in the US are diagnosed each year with infantile spasms. Infantile spasms is slightly more common in males, accounting for about 60% of cases, and a family history exists in 3% to 6% of cases ³⁾.

Infantile spasms are so uncommon that most pediatricians will see only one or two infantile spasms cases during all the years of practice. Also infantile spasms often looks similar to common disorders such as a normal startle reflex, colic, or reflux.

It is very important to recognize that a child has infantile spasms as soon as it begins because ⁴⁾:

• there are medications that may control the spasms
• the longer the spasms last before they are treated and controlled, the poorer the child may do developmentally

Unfortunately, children who develop infantile spasms are at great risk for developmental disability and autism, but some children will do well if they are treated early. Because the spells may be subtle, the diagnosis may be delayed for weeks or months

Infantile spasms was originally classified as a generalized epilepsy according to the 1989 International Epilepsy Classification ⁵⁾. However, using the revised classification based on the 2001 International League Against Epilepsy report, this epileptic syndrome can be classified as: Level I (ictal phenomenology): clinical spasms, flexor, extensor, mixed or subtle; Level II (epilepsy seizure type): epileptic spasms; Level III (epilepsy syndrome): infantile spasm syndrome ⁶⁾.

Determining the cause of infantile spasms is very important because it affects treatment and prognosis. After careful evaluation, the underlying cause can be identified in more than 70% of cases ⁷⁾. There are dozens of disorders that are known to cause infantile spasms. When neurologists are able to identify the cause, it is labeled “symptomatic.” It is essential that an appropriate diagnostic evaluation be performed in every child. A diagnosis is important because it leads to specific treatment that may improve the long-term developmental outcome. In fact, some children with infantile spasms may ultimately lead normal lives, but only if they are diagnosed and treated correctly.

The goal of treatment for infantile spasms is for the seizures to stop and the EEG to improve (hypsarrhythmia should resolve). Standard first-line treatments for infantile spasms include several forms of hormonal therapy (including adrenocorticotrophic hormone [ACTH] or prednisone) or the anti-seizure medication vigabatrin (GABA aminotransferase inhibitor) ⁸⁾. These treatments are highly effective but have serious side effects and should be administered in consulataton with a pediatric neurologist. Some children have spasms as the result of brain lesions, and surgical removal of these lesions may result in improvement. When standard treatments do not lead to improvement, other options such as the ketogenic diet and anti-seizure medications are considered. Regardless of the specific treatment chosen, it is critical to begin therapy as soon as possible. Ongoing infantile spasms (and hypsarrhythmia) have the potential to adversely impact all aspects of brain development.

To help make clear what infantile spasms look like, please watch these videos of a child having infantile spasms.

What do infantile spasms look like?

Infantile spasms were first described by the English physician, Dr. W.J. West in 1841 ⁹⁾. His description is as accurate today as it was then. It is a remarkable report because Dr. West was describing his own son and he was asking for help. The following is a quote from Dr. West’s report describing his son:

• “The child is now a year old; it was a remarkably fine, healthy child when born, and continued to thrive until he was four months old. It was at this time that I first observed slight bobbings of the head forward, which I then regarded as a trick, but were, in fact, the first indications of disease”

Like Dr. West’s son, many children with infantile spasms appear to be normal until the spasms begin. It seems that he was not concerned when he first saw the spasms because they did not appear to be serious. Just like Dr. West, parents today often tell us that they were not concerned at first. But, as the spasms become more obvious they realize that this is something serious. Dr. West then described what happened to his son over the next few months.

• “for these bobbings increased in frequency, and at length became so frequent and powerful, as to cause a complete heaving of the head forward toward his knees, and then immediately relaxing into the upright position: these bowings and relax things would be repeated alternately at intervals of a few seconds, and repeated from 10 to 20 or more times in each attack, which attack would not continue for more than two or 3 minutes; he sometimes has two, three, or more attacks in the day; they come on whether sitting or lying; just before they come on, he is all alive and in motion, making a strange noise, and then all of a sudden down goes his head and upwards his knees; he then appears frightened and screams out”

The spasms usually become more obvious as they did in this case. Sometimes they remain subtle, maybe just a brief head nod but nothing else. Dr. West‘s son had what’s called “flexor spasms” where the child’s head goes forward and the legs come up. The arms usually flare out from the body as the head and body come forward. Sometimes spasms occur with the head going back and the legs straightening out. These are called “extensor spasms.” Each spasm episode lasts just a second or two but they often come in clusters. Although the spasms may happen as single jerk event, clusters are more common and often occur on awakening in the morning or after a nap. By the time Dr. West wrote about his son, he had been having the spasms for several months and the effect on his development was obvious, as Dr. West wrote:

• “at one time he looked pale and exhausted, but lately he has regained his good looks, and independent of this affection, is a fine growing child, but he neither possesses the intellectual vivacity or the power of moving his limbs, a child his age; he never cries at the time of the attacks, or smiles or takes any notice, but looks placid and pitiful, yet his hearing and vision are good; he has no power of holding himself upright or using his limbs, and his head falls without support”

Unfortunately for Dr. West’s son, there were no effective treatments available in 1841 so he had the worst possible outcome. In addition to not developing mentally, he also seemed to be very weak and was not even able to control his head when he was seated.

Infantile spasms prognosis

The prognosis for children with infantile spasms is largely dependent on the underlying cause. The intellectual prognosis for children with infantile spasms is generally poor because many babies with infantile spasms have neurological impairment prior to the onset of spasms. Children who have rapid initiation of treatment, normal development prior to infantile spasms, and no identifiable cause may do well. Infantile spasms usually resolves by mid-childhood, but more than half of the children with infantile spasms will develop other types of seizures such as Lennox-Gastaut syndrome, an epileptic disorder of later childhood. In addition, children with infantile spasms are at a higher risk for autism. Shorter duration between the onset of infantile spasms and initiation of standard treatment appears to lead to an improved outcome; therefore early recognition of the seizures and early treatment are essential.

The spontaneous remission rate of infantile spasms in limited natural history studies is 30%. Although clinical spasms and the typical EEG pattern disappear by 3 to 4 years of age, up to 60% of children with infantile spasms go on to develop other types of seizures. The long-term prognosis for infantile spasms in terms of neurodevelopmental outcomes and development of other types of seizures remains dismal, although most studies reported better neurodevelopmental outcomes in idiopathic or cryptogenic cases.

The United Kingdom Infantile Spasms Study reported on the long-term outcomes of 77 patients with infantile spasms at 4 years and noted that whereas there was no significant difference between patients treated with either hormonal therapy or vigabatrin in outcomes for either neurodevelopmental delay or epilepsy, those patients with cryptogenic infantile spasms who received hormonal therapy had higher mean Vineland Adaptive Behavioral Scale scores ¹⁰⁾. Also, a 3.9-point decrease in mean Vineland Adaptive Behavioral Scale score was observed for each increase in category of lead-time duration after controlling for the effects of treatment and etiology ¹¹⁾.

The 2012 updated guideline recommended a shorter lag time to treatment of infantile spasms with either hormonal therapy or vigabatrin to possibly improve long-term developmental outcomes ¹²⁾.

These data emphasize the importance of prompt diagnosis and urgent treatment of children with infantile spasms to improve their long-term outcomes.

Dr. Riikonen ¹³⁾ from Finland has followed 214 infantile spasms patients for 20–35 years. She has collected the best long-term follow-up studies of these patients. In her series, nearly 1/3 of the patients died during the follow-up period; many in the first 3 years of life. Many of the 24 patients who died by age 3 died of complications of therapy with ACTH. During the time the study was done, patients were treated with high-dose ACTH for extended periods of time. This caused immunosuppression , which greatly increased the risk of infection such as pneumonia. The current approach to treatment of using ACTH or prednisolone for much shorter periods of time is associated with a much lower risk of death. Of the 147 surviving patients, 25 (17%) had a favorable developmental outcome with an IQ of 85 or greater. Eleven others were somewhat lower with an IQ of 68–84. Thus, of the 214 patients diagnosed with infantile spasms, 31% died, 45% were developmentally disabled, but 24% had a reasonably favorable outcome. The outcome is dependent on two major factors. First and foremost is the underlying etiology or cause. Some etiologies will lead to death or mental retardation, whether or not the patient developed infantile spasms. However, children with cryptogenic infantile spasms or infantile spasms that due to treatable causes, such as focal cortical dysplasia, may have a normal or near normal developmental outcome if seizures are controlled. Thus, the goal of therapy is to achieve control as soon as possible, especially for children who may have the potential for normal intellectual development.

Infantile spasms symptoms

Clinically, the spasms appear in clusters and are characterized by brief, sudden contractions of the axial musculature. The clusters may occur several times daily, with up to 100 spasms per day. They appear to be temporally related to sleep, tending to occur as the infant falls asleep or awakens. Depending on the muscle groups involved, the spasms can be further subdivided into flexor, extensor, or mixed. The type of spasms may also be influenced by the position of the body at the time the spasms occur.

In flexor spasms, the infant appears to be in a self-hugging posture with sudden adduction of the arms. The abdominal muscles may be involved, with the infant bending at the waist; the term jackknife seizureis sometimes used for this manifestation. The combination of jackknife seizure plus adduction of the arms with or without neck flexion is called salaam seizures.

Extensor spasms look similar to an exaggerated Moro reflex. Mixed spasms are a combination of flexion of the neck, trunk, and arms, with leg extension. In some cases, the spasms may be subtle, manifesting as head nods and clusters of wide eye opening with eye deviation.

The cause of infantile spasms does not point to the clinical signs and symptoms, or appearance, of the spasms; however, the presence of asymmetry may indicate focal cortical pathology as a cause.

Developmental regression is almost always seen at the onset of infantile spasms, with decreased visual alertness often being the first symptom. The vast majority of children develop significant cognitive impairment when followed long-term. In many cases, the spasms evolve into other types of medically refractory epilepsy as the children grow older.

Infantile spasms causes

Infantile spasms may be classified into three groups: symptomatic, cryptogenic, and idiopathic. The term symptomatic is used to describe cases in which there are structural brain abnormalities or metabolic causes seen in a child with preexisting developmental delay. When there are no apparent causes identified in a child with developmental delay or some other neurologic impairment before the onset of spasms, the term cryptogenic infantile spasms is used. Idiopathic infantile spasms are those in which the child is developmentally normal, with a normal neurologic exam prior to onset of infantile spasms ¹⁴⁾.

Cryptogenic cases constitute up to 15% of infantile spasms cases. The number of symptomatic cases has increased over the years due to advancement in neuroimaging technology, better metabolic testing, and the availability of genetic testing ¹⁵⁾.

Symptomatic cases are further subdivided into prenatal, perinatal, and postnatal, depending on the timing of presumed causes. There are numerous disorders associated with symptomatic infantile spasms, but major categories include chromosomal abnormalities and genetic syndromes, disorders of cortical development, infections, metabolic conditions and vitamin deficiencies, trauma, vascular insults, and tumors. Tuberous sclerosis is a major symptomatic cause of infantile spasms, with up to 50% of patients with TS presenting with infantile spasms between 4 and 6 months of age. Several gene mutations that have been associated with infantile spasms include ARX, CDKL5, FOXG1, GRIN1, GRIN2A, MAGI2, MEF2C, SLC25A22, SPTAN1, and STXBP1. Children with these genetic disorders were formerly classified as cryptogenic or idiopathic. Classification of cases into these two categories will continue to dwindle as more and more genetic causes of infantile spasms are revealed by more sophisticated genetic screening. In fact, new insights into molecular genetic testing imply that all forms of infantile spasms may actually be symptomatic, and the International League Against Epilepsy has recently recommended replacing the symptomatic, cryptogenic, and idiopathic classification system of epilepsy syndromes. However, most studies on treatment and long-term outcomes of infantile spasms subdivide cases into either symptomatic or cryptogenic, and these studies do point to the cause as a contributing factor for long-term neurodevelopmental outcomes ¹⁶⁾.

The cause of infantile spasms (West syndrome) is varied (see Figure 1 below), with the majority (~60%) being due to structural-metabolic causes while the rest are either of unknown cause or linked to genetic defects ¹⁷⁾. The unknown cause group is the infants in which no structural-metabolic or genetic cause can be identified with the existing diagnostic tests. With the recent advances in methods for genetic diagnosis, an increasing number of associations of infantile spasms (West syndrome) with genetic defects has been made, which is now estimated to encompass the 12% of infants with infantile spasms (West syndrome) ¹⁸⁾. The list of known genetic associations with infantile spasms can be found here (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4458451/bin/NIHMS689516-supplement-2.docx). The cause influences treatment response. A known structural-metabolic underlying cause diminishes significantly the chance of treatment response while the unknown cause group bears the best prognosis ¹⁹⁾. On the other hand, knowing the cause may guide treatment selection, as is the case with tuberous sclerosis which is particularly responsive to vigabatrin ²⁰⁾.

Figure 1. Infantile spasms causes and diagnostic steps

[Source ²¹⁾]

Infantile spasms diagnosis

Because of the critical importance of early treatment, children presenting with infantile spasms require prompt and comprehensive diagnostic evaluation. This includes a complete history, physical and neurologic examination, and an urgently obtained EEG. The latter is critical because the ultimate diagnosis of infantile spasms is made by the clinical history coupled with the EEG findings.

Doctors follow a standard evaluation process to try to identify the underlying cause of the infantile spasms. This process, as noted in the figure below, includes different steps a neurologist will perform to identify disorders that are associated with infantile spasms by:

• First, taking a history
• Second, a careful physical and neurologic examination
• Third, doing a magnetic resonance imaging (MRI) scan.
• Fourth, doing a electroencephalogram (EEG) test.
• Fifth, doing metabolic and genetic test. There are many metabolic and genetic disorders that have been associated with infantile spasms, but they are very rare.

History of the child

The first step is a careful history. Sometimes the underlying cause of infantile spasms is determined by taking a careful history of the patient. The history includes all information related to the pregnancy, labor and delivery as well as all of the events, including developmental milestones, which have occurred prior to the time of evaluation for the infantile spasms. A child may be developing normally, but then development stops, or even reverses. If that happens, it is an important clue. Some children may have seizures that occurred prior to the infantile spasms. Sometimes the seizures begin on one side of the body and that is also an important clue to understanding possible causes. Although there are many disorders associated with infantile spasms that may be identified by taking a careful history, two stand out as particularly important:

1. A history of brain injury from lack of oxygen
2. Brain injury from infection such as meningitis or encephalitis.

A child may be developing normally, but then development stops, or even reverses. If that happens, it is an important clue.

Physical and neurologic examination

The second step is a careful physical examination and neurologic examination of the child. Many patients may have been developmentally delayed prior to the onset of spasms. Several underlying disorders can be identified by careful examination, such as:

• Cerebral palsy: Some children may have signs of cerebral palsy. These symptoms would be a clue of a brain problem that occurred during development or at the time of birth, such as stroke causing brain damage.
• Down syndrome: If Down syndrome had not been identified prior to presentation with infantile spasms it will be apparent on the physical examination.
• Tuberous sclerosis: An examination of the skin, especially the characteristic of “ash leaf” spots, is evidence of tuberous sclerosis. Ash leaf spots are small areas of skin that appear to be white compared to the rest of the skin because they lacked normal pigment. Tuberous sclerosis is one of the more common associated disorders. Tuberous sclerosis also has very characteristic changes on the MRI brain scan that are diagnostic.

Several other disorders can be diagnosed by skin examination including neurofibromatosis and incontinentia pigmenti.

Neuroimaging

The third step is an MRI scan. Neuroimaging has been an important advancement in the last several decades in the diagnosis of the underlying etiologies or causes of infantile spasms. Both the MRI scan and computed tomography (CT) scan have been used to detect brain abnormalities in children with infantile spasms. However, the MRI scan is much more sensitive and more likely to discover an abnormality of the brain than the CT scan. A large list of neurologic abnormalities can be seen on MRI scan (including developmental brain abnormalities) and evidence of brain injury events (such as brain injury from lack of oxygen, trauma, brain tumor, or injury from past infection).

However, it is important to note that MRI performed in a child less than 2 years of age can still miss subtle cortical migrational anomalies due to immaturity of the white matter. Therefore, a child who has spasms in addition to other neurodevelopmental abnormalities, but a normal MRI scan in the first year of life, should have a repeat MRI at 2 years of age or older ²²⁾. Interictal positron emission tomography (PET) may detect areas of hypometabolism, which may correlate with cortical malformation. PET is not used in the routine diagnostic evaluation of infantile spasms; however, PET may be valuable in a child with spasms for whom the MRI is normal but a structural brain lesion is suggested by the asymmetry of spasms and a focally abnormal EEG pattern.

Once the doctor has completed a careful history, physical and neurologic examination, and performed an MRI scan, almost all of the underlying disorders that doctors know of which are associated with infantile spasms will have been identified.

Electroencephalogram (EEG)

Most children who have infantile spasms will have a very abnormal electroencephalogram (EEG) pattern called hypsarhythymia or modified hypsarhythmia. Hypsarhythmia is a very high-voltage, disorganized and asynchronous high-amplitude background with spikes and slow waves pattern of EEG. The hypsarrhythmia pattern is not present during the entire EEG in many cases. This EEG pattern can be seen in wakefulness and is enhanced during sleep. Therefore, an EEG study to rule out infantile spasms should ideally include both awake and sleep recording. A less chaotic pattern, called modified hypsarhythmia, actually may be more common than hypsarhythmia. Hypsarhythmia or modified hypsarhythmia is seen in about 2/3 of cases. Some children may have an EEG pattern that is less dramatic than hypsarhythmia or modified hypsarhythmia and in those cases, it is very important to see what the EEG does when the child has a cluster of spasms. At the time of a spasm, the EEG usually flattens out for a very brief time. This is called an “electrodecremental response” or burst suppression, which is a high-voltage sharp or slow-wave discharge followed by generalized voltage attenuation or flattening. In addition to hypsarrhythmia and burst suppression, there are several additional, less dramatic ictal EEG patterns associated with infantile spasms, including combinations of generalized sharp and slow-wave discharges and electrodecremental fast activity. Thus, the diagnosis of infantile spasms can be confirmed by observing either hypsarhythmia, modified hypsarhythmia or an electrodecremental response. Many patients will have all three.

• The diagnosis of infantile spasms can be confirmed by observing the patterns of hypsarhythmia, modified hypsarhythmia or an electrodecremental response on an EEG. The seizures’ appearance and EEG are so distinct that the clinical diagnosis of infantile spasms can be made with certainty in the most cases. Once it’s recognized, the diagnosis of infantile spasms is usually easy, but determining what caused the spasms may be difficult.
• It is important to emphasize that all of these abnormal EEG patterns represent a dynamic continuum that can occur at any point along the natural history of infantile spasms. Therefore, an EEG diagnosis of hypsarrhythmia is not required for diagnosing infantile spasms and initiating treatment. Any child with the clinical signs and symptoms of infantile spasms as described previously and who has any epileptiform activities on his or her EEG, be it hypsarrhythmia or some other paroxysmal abnormality, merits urgent treatment of the spasms. Conversely, if the child appears to be having infantile spasms by history but results from a waking and sleeping EEG are normal, the child does not have infantile spasms but rather could be experiencing a benign infantile myoclonus.

If the electroencephalogram (EEG) is normal, the diagnosis of infantile spasms should be reconsidered because there are benign disorders that may appear clinically similar to infantile spasms (for example, benign infantile myoclonus or benign familial infantile convulsions).

Metabolic and genetic studies

Finally, if the history, physical examination, neurologic examination, EEG and MRI scan do not reveal the underlying cause, then the genetic/metabolic evaluation may be considered. More than 50 genetic/metabolic diseases have been associated with infantile spasms. It is not always necessary to do the complete metabolic/genetic workup on every child. If the history or exam suggests the possibility of a metabolic or genetic disorder then the treating physician will undertake the evaluation. A rare cause of infantile spasms is a disorder called “pyridoxine (vitamin B6) dependent seizures.” It is sometimes useful to administer a trial of intravenous pyridoxine. If that is unsuccessful, blood and urine tests for metabolic or genetic diseases may be performed. A spinal tap (lumbar puncture) may be necessary since some disorders can be detected only in spinal fluid. If, at the conclusion of the history, EEG, MRI, and metabolic testing, no etiology has been identified, the cause of infantile spasms is then called “cryptogenic .” Cryptogenic means that the cause is hidden. It does not mean that there is not a cause; it just means that your doctors don’t know all the causes yet and don’t have a way to find them all.

More than 50 genetic/metabolic diseases have been associated with infantile spasms.

Blood and urine tests are performed for detecting a potential genetic, metabolic, or infectious etiology that can cause symptomatic infantile spasms. These tests also provide baseline results before initiation of treatment.

Blood tests should include but not be limited to complete blood and differential count; tests of glucose, electrolyte, pH, lactate, blood urea nitrogen, creatinine, aspartate aminotransferase, alanine transaminase, bilirubin, and alkaline phosphatase levels; test of thyroid function; and screens of serum amino acid, toxoplasma, and cytomegalovirus IgG and IgM or polymerase chain reaction (or both).

Urine tests should include urinalysis and amino acid and organic acid screens.

Electrocardiogram (ECG) and chest x-ray should be performed, especially when cardiac examination is abnormal. Consultations with ophthalmology, cardiology, and genetics can also be requested as needed.

Chromosomal studies with microarray and genetic tests for infantile epileptic encephalopathies may be indicated when there is a family history or when the above-listed blood, urine, and neuroimaging tests are negative.

Infantile spasms treatment

The goal of infantile spasm therapy is to achieve seizure control as soon as possible. This is very important because if the seizures cannot be controlled, the child is unlikely to develop typically. Unfortunately, even a 50%-90% reduction in the number of seizures does not provide for typical development. For example, if a child’s infantile spasms disorder was causing 100 spasms a day before treatment, but then only has one spasm per day after treatment, his therapeutic intervention is still considered unsuccessful. Unfortunately, for many patients, the underlying disorder does not allow for normal development even if the spasms are completely controlled (for example: brain damage from lack of oxygen or infection). Nevertheless, seizure control should still sought because it greatly improves the patient’s and the parents’ lives. For other patients, there may be an opportunity to greatly improve the developmental outcome. The patients with the best prognosis are those with a cryptogenic etiology and possibly some patients with tuberous sclerosis or a localized cortical dysplasia. In either case, the treatment that gives the child the best chance to achieve complete control of spasms is the treatment of choice. On rare occasions, the testing will reveal a metabolic or genetic disorder that has a specific therapy which would then be the treatment of choice.

Anticonvulsant medications

Medical treatment options are somewhat different for infantile spasms than for other seizure types. There are only two drugs that are approved by the FDA for the treatment of infantile spasms:

• Adrenocorticotropic hormone (ACTH)
• Vigabatrin

There is considerable variation in the management of infantile spasms, as evidenced by the US Consensus Report and a recent survey done on the current evaluation and treatment of infantile spasms among members of the Child Neurology Society ²³⁾. According to these sources, most neurologists use adrenocorticotrophic hormone (ACTH) as their preferred first-line treatment for infantile spasms not caused by tuberous sclerosis and vigabatrin as the first-line treatment of infantile spasms caused by tuberous sclerosis ²⁴⁾.

Medications that are used to treat older children or adults with epilepsy, such as phenobarbital, carbamazepine, or phenytoin, are rarely helpful. There is some evidence that one or two of the newer drugs or the ketogenic diet may be effective in some patients. So, even patients who fail treatment with ACTH and with vigabatrin may occasionally be controlled with other therapies. Therefore, it is very important to keep trying if the first treatments don’t seem to be successful.

First line medical therapies

Adrenocorticotropic Hormone (ACTH)

ACTH is the oldest of the approved medications for infantile spasms. It was the first drug that ever was shown to be successful in treating infantile spasms. In 1958, Sorel reported administering ACTH to seven patients, four of whom responded within a few days and only one of whom had no response at all. ACTH was used for more than 50 years before it was approved by the FDA in 2010 for the treatment of infantile spasms. One drawback from the use of ACTH is that it must be given by intramuscular injection once or twice each day. One or both parents are taught how to give the injections so that the shots can be given at home.

Questions regarding the optimal dose, formulation, and duration of ACTH treatment remain, although the 2012 updated guideline reported that low-dose ACTH is probably as effective as high-dose ACTH for short-term treatment of infantile spasms ²⁵⁾.

ACTH is a very powerful medication and has many of side effects. The majority of children will become very hungry and gain weight. Most become very irritable. More serious side effects include:

• High blood pressure (up to 37%)
• Irritability (37%-100%)
• Infection (14%)
• Cerebral atrophy (62%)
• Decreased glucose levels in the blood
• Stomach ulcer
• Growth retardation
• Heart problems
• Immunosuppression (difficulty fighting infection)

Higher dosage and longer duration of treatment correlate with higher incidence of side effects.

Different epilepsy centers show considerable variability in dosage (high vs low), formulation (natural ACTH in the United States vs synthetic ACTH in Canada, Japan, and Europe), and duration of therapy.

In one study, the risk of serious side effects with ACTH was 43%. ACTH is more likely to be effective at higher doses than lower doses. In addition, the more serious complications occur when the children have been on the medication for an extended period of time. Thus, by treating at high doses and by keeping the duration as short as possible, the child has the best chance for controlling the spasms and the risk of serious complications can be decreased. Children being treated with ACTH must see their doctors frequently for regular blood pressure measurements and blood tests to minimize the risks. The chance that ACTH will control the spasms at the highest doses may be as high as 80+%. Some children may have a return of the spasms when the medication has been tapered and stopped. Whether the medication should be repeated a second time is not clear. If ACTH treatment has not been successful within two weeks, it should be rapidly tapered and stopped and another medication should be tried.

Vigabatrin

In 1991, it was reported that a new medication, vigabatrin, showed remarkable efficacy with infantile spasms. Sixty-eight patients who had failed other therapies were treated with vigabatrin as add-on therapy, and 29 of them (43%) showed complete resolution of the spasms. It was also noted that 12 of 14 patients who had tuberous sclerosis responded with complete control. There is some evidence that vigabatrin also may improve developmental outcome in patients with tuberous sclerosis. It is important to understand how vigabatrin compares with ACTH. Vigevano et al. performed a study of children with newly diagnosed infantile spasms. The patients were given either ACTH or vigabatrin. Eleven of 23 vigabatrin patients responded (1 later relapsed) compared with 14 of 19 patients treated with ACTH (6 later relapsed). After relapses were taken into account, the long-term response rate was similar for both medications. In that study, ACTH was more effective for patients with perinatal hypoxic ischemic encephalopathy. Vigabatrin generally is well tolerated in young children. Most side effects are not serious. There are reports of decreased muscle tone, sleepiness, or difficulty sleeping. However, there is one side effect that is potentially more serious – visual field constriction (tunnel vision). Blindness has not been reported and central vision appears to be unaffected. The visual loss is usually very subtle; most people who had it were not aware that it had occurred until special testing was performed. It was hard for people to realize that they had a problem, so it took more than a decade to recognize that it occurs. There have been many reports showing that peripheral visual fields are constricted in 15 to 50% of adult patients. It is not known if visual field constriction occurs in very young children because there is no effective method of testing for it. However, given the tragic nature of infantile spasms, even if it is proven to occur in infants, visual field constriction may be an acceptable side effect to trade for seizure control and an improved opportunity for normal development. Despite the visual field issue, many pediatric epileptologists consider vigabatrin to be the drug of choice for children with infantile spasms that are due to tuberous sclerosis and for other conditions as well. Whether one chooses to treat initially with ACTH or vigabatrin is a decision made by the parents in consultation with their physician. There are circumstances where ACTH may be the best medication to choose and other circumstances where vigabatrin would be best. Most doctors recommend vigabatrin for patients who have infantile spasms associated with tuberous sclerosis.

Baseline visual field testing or, in the case of infants, electroretinography, should be done before initiation of treatment and regularly thereafter to monitor for retinal toxicity. The initial dose of vigabatrin is 50 mg/kg body weight which is rapidly titrated up to 150 mg/kg body weight divided twice a day. In order to minimize the risk of retinal toxicity, vigabatrin should be given for no longer than 6 months.

Prednisone

A possible alternative to the use of ACTH is an oral medication called prednisone or prednisolone. For many years it was not clear whether one was better than the other. Several studies showed the high-dose ACTH may be superior to what was then used as the dosage for prednisone. Some physicians are now using a much higher dose of prednisolone and finding that it is successful in treating many patients with infantile spasms. A recent study reported using 8 mg per kilogram of prednisolone for two weeks and if the medication was not successful , then trying ACTH. The main advantage of prednisolone is that it can be given orally whereas the ACTH requires daily injections.

Second line medical therapies

Pyridoxine

Pyridoxine (vitamin B6) dependency is a very rare cause of infantile spasms. A trial of 100-mg pyridoxine given intravenously should be administered if diagnosis remains in doubt after the history, examination, and MRI scan have been performed. An immediate normalization of the EEG suggests pyridoxine-dependent epilepsy. Continued oral administration of high doses of pyridoxine also may be effective for some patients who do not have pyridoxine-dependent seizures. In Japan, high-dose pyridoxine is considered the initial drug of choice by many pediatric neurologists, with reports that approximately 15% respond. While this response rate is lower than either ACTH or vigabatrin, pyridoxine is their first choice based on the safety profile. Side effects include loss of appetite, irritability, and vomiting—all of which are relatively common but modest compared with those associated with ACTH or vigabatrin. Pyridoxine has not found support outside of Japan and a few other epilepsy centers. But, given the low risk associated with its use, it seems reasonable to give patients a 1 to 2 week trial of 100 to 400-mg pyridoxine before starting other medications. If these “standard” medications fail, other therapies must be considered, including other antiepileptic drugs (valproate [valproic acid], topiramate, zonisamide) or vitamin B6 ²⁶⁾.

Valproic Acid

Valproic acid probably has the best anecdotal or unscientific evidence of success in treatment, but there have been no prospective randomized studies of efficacy for infantile spasms. Doses range from 20 mg/kg/day to 100 mg/kg/day. Although none of the reported patients developed liver failure, it nevertheless is a risk in children less than 2 years of age and should be used with caution for children with infantile spasms. This is a difficult limitation to valporic acid’s use because almost all patients are less than 2 years of age. Thus, the risk/benefit ratio should be determined.

Clonazepam

One of the earliest non-steroid treatments for infantile spasms were with the benzodiazepines , including clonazepam and nitrazepam. Nitrazepam was never approved for use in the US, so clonazepam is the only one available that has evidence of efficacy. Clonazepam was first reported to be helpful in a few patients with infantile spasms in the 1960’s. It is rarely used today because there are so many better medications. Several of the new anticonvulsants have some evidence of efficacy.

Zonisamide

Zonisamide has shown some promise as an effective therapy for infantile spasms, but there have been no controlled or comparison trials to date. The Japanese experience suggests that zonisamide may be effective in about a 1/3 of patients. A recent report indicated that 5 of 25 patients with infantile spasms had a complete clinical and electrographic response (EEG pattern) to zonisamide within 1 to 2 weeks, with doses ranging from 8 to 32 mg/kg/day. Zonisamide is generally well tolerated. If the 30% or greater efficacy rates hold up in controlled studies, zonisamide could become a first-line therapy. However, most doctors are not finding the success rate to be that high.

Topiramate

In one study, topiramate was shown to be effective in 4 of 11 intractable infantile spasm patients in doses up to 25 mg/kg/day. Another study reported that topiramate reduced seizures in 43% of 14 infantile spasms patients, but 29% were made worse and none became seizure free.

Lamotrigine

Lamotrigine is another of the newer antiepileptic drugs with some anecdotal or scientific evidence of efficacy for infantile spasms, although there are no prospective controlled trials. One report of 3 patients who did not have a successful response to vigabatrin and ACTH treatment responded to lamotrigine after 1 dose. The usual dose of lamotrigine is 6 to 10 mg/kg/day. The major side effect is rash, which is dependent to some extent on how rapidly the dose is increased. The usual recommendation is to increase the dose slowly over 2 months to the minimum expected therapeutic dose. Given the severe nature of infantile spasms and the need to achieve control as soon as possible, taking 2 months to get to a therapeutic level obviously decreases the value of lamotrigine as a therapeutic option. However, if the lowest dose is effective, then lamotrigine becomes a drug to try when standard therapies have failed. Finally, there are three non-drug therapies that should be considered as options when other therapies have failed:

• Ketogenic diet
• High-dose intravenous immunoglobulin (IVIG)
• Surgery

Ketogenic Diet

The ketogenic diet is a decades-old therapy that is back in popularity. Two recent retrospective reports of 40 children with infantile spasms show diet may control spasms in 20 to 35% of patients who are intractable to other therapies ²⁷⁾, ²⁸⁾. In the past, there had been a question as to whether children less than 1 year of age could achieve and maintain ketosis. The recent reports indicate that young children can indeed achieve ketosis and may benefit from the diet. Most of the children tolerated the diet well, but there were adverse events, including renal stones, gastritis, hyperlipidemia, and gastroesophageal reflux.

High-dose intravenous immunoglobulin (IVIG)

High-dose intravenous immunoglobulin (IVIG) has been reported to be helpful in a variety of seizure disorders. One study reported that all six children in their study who had cryptogenic infantile spasms achieved complete remission, but only one of five symptomatic patients responded. Intravenous immunoglobulin doses ranged from 100 to 200 mg/kg/dose given every 2 to 3 weeks to 400 mg/kg/day for five consecutive days. Although there is little data, intravenous immunoglobulin could be considered a possible therapeutic option in patients whose other medical therapies have not been successful. However, the actual efficacy is unclear and the most appropriate dosing and duration have not been defined.

Surgery

The final nondrug therapy is removing an abnormal part of the brain (cortical resection). This option should be considered for patients who:

• Have failed other therapies including ACTH and Vigabatrin or both
• Have evidence of structural brain abnormalities in a defined area, such as developmental brain abnormalities, brain damage, or tuberous sclerosis.

Not many years ago, infantile spasms were considered to be a generalized seizure disorder, and thus surgery was not possible. It has become clear in the last several years that in spite of the generalized nature of the seizures, an area of cortical abnormality can often be discovered. Removal of the abnormality may lead to control of seizures and, possibly, improved developmental outcome. The majority of patients who have cortical resection have evidence of focal cortical abnormalities prior to surgical evaluation. For these patients, surgery should be considered early in the course rather than waiting for months or years. Selecting the appropriate candidates for surgery is usually more difficult in infantile spasms than for other types of epilepsy because of the generalized nature of the EEG abnormalities. The following should lead to a referral to a pediatric epilepsy surgery center for further evaluation:

• A careful review of the history (especially history of partial seizures that came first or accompanied infantile spasms)
• The presence of cortical disturbances on MRI scan
• Localized EEG abnormalities that suggest a localized cortical defect.

What is fetal alcohol syndrome

Fetal Alcohol Syndrome is a pattern of abnormalities like a range of mental and physical disorders on the developing unborn baby whose mother who drank alcohol during pregnancy. These effects range from brain damage and poor growth to birth defects and learning problems ¹⁾. Alcohol is known to be what is called a ‘teratogen’. A teratogen is something from outside the body that can cause malformation and problems with the unborn baby. Fetal alcohol syndrome happens when a woman drinks when she’s pregnant. When a woman drinks alcohol, so does her baby. Even small amounts of alcohol will pass across the placenta and to the fetus. The baby’s liver is not developed enough to be able to process the alcohol. Through a number of biological means, alcohol can affect the size, shape, and function of the cells that form the brain, the heart, the kidneys, and all other body organs and systems of the fetus. The alcohol can damage the baby’s brain and organs and can cause other harm. Because brain growth takes place throughout pregnancy, the sooner a woman stops drinking the safer it will be for her and her baby. There’s no cure or specific treatment for fetal alcohol syndrome. The physical defects and mental deficiencies typically last for a lifetime.

There is no known safe amount of alcohol during pregnancy or when trying to get pregnant. There is also no safe time to drink during pregnancy. Alcohol can cause problems for a developing baby throughout pregnancy, including before a woman knows she’s pregnant. All types of alcohol are equally harmful, including all wines and beer.

• In 2015, the American Academy of Pediatrics stated that consuming alcohol at any time during pregnancy causes increased risk of physical and neurocognitive developmental disorders in a child, and that no amount of alcohol is safe to consume during pregnancy.

“Binge drinking” (having 3 or more drinks at a time) is especially dangerous for your baby. It makes the level of alcohol in your blood very high very quickly. Even if you don’t drink every day, you may put your baby at risk for fetal alcohol syndrome if you binge drink.

Drinking alcohol in the first 3 months of pregnancy is the most dangerous. This is when the baby’s brain starts to develop. Alcohol can interfere with the development and cause birth defects. But drinking at any time during pregnancy is not safe and can harm your baby.

A broader term is Fetal Alcohol Spectrum Disorder is a group of conditions that can occur in a person whose mother drank alcohol during pregnancy — this describes any physical or developmental disorders caused by prenatal alcohol exposure. Fetal Alcohol Spectrum Disorder is completely preventable if a woman does not drink alcohol during pregnancy.

The changes depend on the amount, frequency and the timing of the consumption of alcohol by the mother during pregnancy. The first three months of pregnancy is the time in which vital organs like the heart and the kidney are developing. Drinking alcohol during pregnancy can be dangerous to you and your baby. Babies born to mothers who drink during pregnancy may have serious health problems. Fetal alcohol syndrome is one of these problems. Because no amount of alcohol can be considered safe, pregnant women should avoid all alcohol during the entire pregnancy.

Symptoms of fetal alcohol syndrome baby include:

• Poor growth in the womb.
• Small and underweight at birth.
• Small head and eyes.
• Wide-set and narrow eyes
• Abnormal facial features, such as a smooth ridge between the nose and upper lip (this ridge is called the philtrum)
• Shorter-than-average height
• Heart defects, such as a hole in the heart.
• Delayed development.
• Sleep and sucking problems as a baby.
• Vision or hearing problems.
• Low body weight
• Poor coordination
• Hyperactive behavior
• Difficulty with attention
• Poor memory
• Difficulty in school (especially with math)
• Learning disabilities
• Speech and language delays
• Intellectual disability or low IQ
• Poor reasoning and judgment skills
• Sleep and sucking problems as a baby
• Problems with the kidney, or bones

The most serious problem fetal alcohol syndrome can cause is developmental delay. Fetal alcohol syndrome is the leading cause of preventable developmental delays in the United States. Fetal alcohol spectrum is quite a common problem, and is the number one cause of intellectual disability that is not caused by genetic problems. It is also hard to know the exact number of children with fetal alcohol spectrum. Across the world, the number of children reported to be born with fetal alcohol spectrum is between 0.5-5 per 1000 births depending on the country. It is also very different in different parts of each country and can be hard to accurately get the numbers on.

Figure 1. Fetal alcohol syndrome face

As fetal alcohol syndrome babies grow older, these children may have behavior problems. They may experience learning disabilities, trouble with memory and attention, and hyperactivity. Symptoms tend to get worse as the child grows older. The cost factor of raising a child with an fetal alcohol spectrum disorder is significant. Researchers have found that, for a child with identified fetal alcohol syndrome, incurred health costs were nine times higher than for children without an fetal alcohol spectrum disorder. The lifetime cost of caring for a person with fetal alcohol syndrome is estimated to be at least $2 million, and the overall annual cost of fetal alcohol spectrum disorder to the U.S. healthcare system to be more than $6 billion.

Fetal alcohol spectrum disorders last a lifetime. There is no cure for fetal alcohol spectrum disorders, but treatments can help. These include medicines to help with some symptoms, medical care for health problems, behavior and education therapy, and parent training. A good treatment plan is specific to the child’s problems. It should include close monitoring, follow-ups, and changes when needed.

Certain “protective factors” can help reduce the effects of fetal alcohol spectrum disorders and help people who have them reach their full potential. They include

• Diagnosis before 6 years of age
• Loving, nurturing, and stable home environment during the school years
• Absence of violence around them
• Involvement in special education and social services.

Fetal alcohol spectrum disorders

The range of consequences from drinking alcohol during pregnancy are collectively called fetal alcohol spectrum disorders, as not all signs and symptoms are present in all children with the disorder. This range includes:

• Fetal alcohol syndrome —Fetal alcohol syndrome represents the most involved end of the fetal alcohol spectrum disorder. Fetal death is the most extreme outcome from drinking alcohol during pregnancy. People with fetal alcohol syndrome might have abnormal facial features, growth problems, and central nervous system (CNS) problems. People with fetal alcohol syndrome can have problems with learning, memory, attention span, communication, vision, or hearing. They might have a mix of these problems. People with fetal alcohol syndrome often have a hard time in school and trouble getting along with others.
• Alcohol-related neurodevelopmental disorder —People with alcohol-related neurodevelopmental disorder might have intellectual disabilities or behavioral and learning problems caused by drinking alcohol during pregnancy. They might do poorly in school and have difficulties with math, memory, attention, judgment, and poor impulse control.
• Alcohol-related birth defects — People with alcohol-related birth defects might have problems with the heart, kidneys, or bones or with hearing. They might have a mix of these.
• Partial fetal alcohol syndrome — presence of some signs and symptoms of fetal alcohol syndrome caused by drinking alcohol during pregnancy, but the criteria for the diagnosis are not met
• Neurobehavioral disorder associated with prenatal alcohol exposure — A child or youth with neurobehavioral disorder associated with prenatal alcohol exposure will have problems in three areas:
  1. Thinking and memory, where the child may have trouble planning or may forget material he or she has already learned,
  2. Behavior problems, such as severe tantrums, mood issues (for example, irritability), and difficulty shifting attention from one task to another, and
  3. Trouble with day-to-day living, which can include problems with bathing, dressing for the weather, and playing with other children. In addition, to be diagnosed with neurobehavioral disorder associated with prenatal alcohol exposure, the mother of the child must have consumed more than minimal levels of alcohol before the child’s birth, which American Psychiatric Association ²⁾ defines as more than 13 alcoholic drinks per month of pregnancy (that is, any 30-day period of pregnancy) or more than 2 alcoholic drinks in one sitting.

If one child in a family is diagnosed with fetal alcohol syndrome, it may be important to evaluate his or her siblings to determine whether they also have fetal alcohol syndrome, if the mother drank alcohol during these pregnancies.

Fetal alcohol syndrome effects

A diagnosis of fetal alcohol syndrome requires the presence of all three of the following findings:

1. All three facial features
2. Growth deficits
3. Central nervous system problems. A person could meet the central nervous system criteria for fetal alcohol syndrome diagnosis if there is a problem with the brain structure, even if there are no signs of functional problems.

Following is an overview of the diagnostic guidelines for fetal alcohol syndrome. These criteria have been simplified for a general audience. They are listed here for information purposes and should be used only by trained health care professionals to diagnose or treat fetal alcohol syndrome.

Healthcare professionals look for the following signs and symptoms when diagnosing fetal alcohol syndrome:

1. Abnormal facial features
   • A person with fetal alcohol syndrome has three distinct facial features:
   • Smooth ridge between the nose and upper lip (smooth philtrum)
   • Thin upper lip
   • Short distance between the inner and outer corners of the eyes, giving the eyes a wide-spaced appearance.
2. Growth problems
   Children with fetal alcohol syndrome have height, weight, or both that are lower than normal (at or below the 10th percentile). These growth issues might occur even before birth. For some children with fetal alcohol syndrome, growth problems resolve themselves early in life.
3. Central nervous system problems
   The central nervous system is made up of the brain and spinal cord. It controls all the workings of the body. When something goes wrong with a part of the nervous system, a person can have trouble moving, speaking, or learning. He or she can also have problems with memory, senses, or social skills. There are three categories of central nervous system problems:
   • Structural: fetal alcohol syndrome can cause differences in the structure of the brain. Signs of structural differences are:
     • Smaller-than-normal head size for the person’s overall height and weight (at or below the 10th percentile).
     • Significant changes in the structure of the brain as seen on brain scans such as MRIs or CT scans.
   • Neurologic:
     • There are problems with the nervous system that cannot be linked to another cause. Examples include poor coordination, poor muscle control, and problems with sucking as a baby.
   • Functional: The person’s ability to function is well below what’s expected for his or her age, schooling, or circumstances. To be diagnosed with fetal alcohol syndrome, a person must have:
     • Cognitive deficits (e.g., low IQ), or significant developmental delay in children who are too young for an IQ assessment.Or
     • Problems in at least three of the following areas:
       • Cognitive deficits (e.g., low IQ) or developmental delays. Examples include specific learning disabilities (especially math), poor grades in school, performance differences between verbal and nonverbal skills, and slowed movements or reactions.
       • Executive functioning deficits: These deficits involve the thinking processes that help a person manage life tasks. Such deficits include poor organization and planning, lack of inhibition, difficulty grasping cause and effect, difficulty following multistep directions, difficulty doing things in a new way or thinking of things in a new way, poor judgment, and inability to apply knowledge to new situations.
       • Motor functioning delays: These delays affect how a person controls his or her muscles. Examples include delay in walking (gross motor skills), difficulty writing or drawing (fine motor skills), clumsiness, balance problems, tremors, difficulty coordinating hands and fingers (dexterity), and poor sucking in babies.
       • Attention problems or hyperactivity: A child with these problems might be described as “busy,” overly active, inattentive, easily distracted, or having difficulty calming down, completing tasks, or moving from one activity to the next. Parents might report that their child’s attention changes from day to day (e.g., “on” and “off” days).
       • Problems with social skills: A child with social skills problems might lack a fear of strangers, be easily taken advantage of, prefer younger friends, be immature, show inappropriate sexual behaviors, and have trouble understanding how others feel.
       • Other problems: Other problems can include sensitivity to taste or touch, difficulty reading facial expression, and difficulty responding appropriately to common parenting practices (e.g., not understanding cause-and-effect discipline)
4. Mother’s Alcohol Use during Pregnancy
   Confirmed alcohol use during pregnancy can strengthen the case for fetal alcohol syndrome diagnosis. Confirmed absence of alcohol exposure would rule out the fetal alcohol syndrome diagnosis. It’s helpful to know whether or not the person’s mother drank alcohol during pregnancy. But confirmed alcohol use during pregnancy is not needed if the child meets the other criteria.

Fetal alcohol syndrome prognosis

Unfortunately there is no treatment for fetal alcohol syndrome that can cause a total cure. While some of the physical problems, such as heart defects, can be treated surgically, the only way that a child can cope with the effects on the brain are through good support from both their family and health professionals. The outcome is generally worse for those children that are more severely affected. The more support and care that they receive, the better the outcomes will be, and plenty of support is available if needed and can be accessed through your local doctor.

I just found out I am pregnant. I have stopped drinking now, but I was drinking in the first few weeks of my pregnancy, before I knew I was pregnant. What should I do now?

The most important thing is that you have completely stopped drinking after learning of your pregnancy. It is never too late to stop drinking. Because brain growth takes place throughout pregnancy, the sooner you stop drinking the safer it will be for you and your baby. If you drank any amount of alcohol while you were pregnant, talk with your child’s health care provider as soon as possible and share your concerns. Make sure you get regular prenatal checkups.

If I drank when I was pregnant, does that mean my baby will have an fetal alcohol syndrome?

If you drank any amount of alcohol while you were pregnant, talk with your child’s health care provider as soon as possible and share your concerns.
You may not know right away if your child has been affected. Fetal alcohol syndrome include a range of physical and intellectual disabilities that are not always easy to identify when a child is a newborn. Some of these effects may not be known until your child is in school.
There is no cure for fetal alcohol syndrome. However, identifying and intervening with children with these conditions as early as possible can help them to reach their full potential.

Is it okay to drink a little or at certain times during pregnancy?

There is no known safe amount of alcohol use during your pregnancy or when you are trying to get pregnant. There is also no safe time to drink when you are pregnant. Alcohol can cause problems for your developing baby throughout your pregnancy, including before you know you are pregnant.
Fetal alcohol spectrum disorders and fetal alcohol syndrome are completely preventable if a woman does not drink alcohol during pregnancy—so why take the risk?

Is it okay to drink alcohol if I am trying to get pregnant?

You might be pregnant and not know it yet. You probably won’t know you are pregnant for up to 4 to 6 weeks. This means you might be drinking and exposing your baby to alcohol without meaning to. Alcohol use during pregnancy can also lead to miscarriage and stillbirth. The best advice is to stop drinking alcohol when you start trying to get pregnant.

Why should I worry about alcohol use if I am not pregnant and not trying to get pregnant?

If you drink alcohol and do not use contraception (birth control) when you have sex, you might get pregnant and expose your baby to alcohol before you know you are pregnant. Nearly half of all pregnancies in the United States are unplanned. And many women do not know they are pregnant right away. So, if you are not trying to get pregnant but you are having sex, talk to your health care provider about using contraception consistently.

I drank wine during my last pregnancy and my baby turned out fine. Why shouldn’t I drink again during this pregnancy?

Every pregnancy is different. Drinking alcohol might affect one baby more than another. You could have one child who is born healthy and another child who is born with problems.

If a woman has an fetal alcohol spectrum disorder, but does not drink during pregnancy, can her child have an fetal alcohol spectrum disorder? Are fetal alcohol spectrum disorders hereditary?

Fetal alcohol spectrum disorders are not genetic or hereditary. If a woman drinks alcohol during her pregnancy, her baby can be born with an fetal alcohol spectrum disorder. But if a woman has an fetal alcohol spectrum disorder, her own child cannot have an fetal alcohol spectrum disorder, unless she drinks alcohol during pregnancy.

Fetal alcohol syndrome complications

Problem behaviors not present at birth that can result from having fetal alcohol syndrome (secondary disabilities) may include:

• Attention deficit/hyperactivity disorder (ADHD)
• Aggression, inappropriate social conduct, and breaking rules and laws
• Alcohol or drug misuse
• Mental health disorders, such as depression, anxiety or eating disorders
• Problems staying in or completing school
• Problems with independent living and with employment
• Inappropriate sexual behaviors
• Early death by accident, homicide or suicide.

Fetal alcohol syndrome causes

The only thing that predisposes a child to having fetal alcohol syndrome is alcohol consumption during pregnancy. Unfortunately, the time when the child is most at risk is early in the pregnancy, even before the woman’s first period is missed.

When you’re pregnant and you drink alcohol:

• Alcohol enters your bloodstream and reaches your developing fetus by crossing the placenta
• Alcohol causes higher blood alcohol concentrations in your developing baby than in your body because a fetus metabolizes alcohol slower than an adult does
• Alcohol interferes with the delivery of oxygen and optimal nutrition to your developing baby
• Exposure to alcohol before birth can harm the development of tissues and organs and cause permanent brain damage in your baby

This can mean that damage is being done without the mother even knowing it. The level of damage done to the unborn child depends on the amount of alcohol drunk.

The more alcohol that is drunk during pregnancy the more severe the effects. However, any amount of alcohol puts your baby at risk. There’s no known lower limit of safe alcohol consumption or whether there is a cut off level where it is okay. Your baby’s brain, heart and blood vessels begin to develop in the early weeks of pregnancy, before you may know you’re pregnant.

Impairment of facial features, the heart and other organs, including the bones, and the central nervous system may occur as a result of drinking alcohol during the first trimester. That’s when these parts of the fetus are in key stages of development. However, the risk is present at any time during pregnancy.

Risk factors for fetal alcohol syndrome

The more alcohol you drink during pregnancy, the greater the chance of problems in your baby. There’s no known safe amount of alcohol consumption during pregnancy.

You could put your baby at risk even before you realize you’re pregnant.

Don’t drink alcohol if:

• You’re pregnant
• You think you might be pregnant
• You’re trying to become pregnant

It is also recommended that the father stop drinking if attempts are being made by the mother to stop drinking, if both partners are actively trying to have a child. This is because alcohol lowers levels of testosterone, reduces the activity of sperm, and can even damage the DNA within the sperm. DNA is what transmits all the information about the father to the baby and so the less damage the better.

Fetal alcohol syndrome prevention

Experts know that fetal alcohol syndrome is completely preventable if women don’t drink alcohol at all during pregnancy.

These guidelines can help prevent fetal alcohol syndrome:

• Don’t drink alcohol if you’re trying to get pregnant. If you haven’t already stopped drinking, stop as soon as you know you’re pregnant or if you even think you might be pregnant. It’s never too late to stop drinking during your pregnancy, but the sooner you stop, the better it is for your baby.
• Continue to avoid alcohol throughout your pregnancy. Fetal alcohol syndrome is completely preventable in children whose mothers don’t drink during pregnancy.
• Consider giving up alcohol during your childbearing years if you’re sexually active and you’re having unprotected sex. Many pregnancies are unplanned, and damage can occur in the earliest weeks of pregnancy.
• If you have an alcohol problem, get help before you get pregnant. Get professional help to determine your level of dependence on alcohol and to develop a treatment plan.

Fetal alcohol syndrome signs and symptoms

The severity of fetal alcohol syndrome symptoms varies, with some children experiencing them to a far greater degree than others. Signs and symptoms of fetal alcohol syndrome may include any mix of physical defects, intellectual or cognitive disabilities, and problems functioning and coping with daily life.

Physical defects

Physical defects may include:

• Distinctive facial features, including small eyes, an exceptionally thin upper lip, a short, upturned nose, and a smooth skin surface between the nose and upper lip
• Be born small.
• Deformities of joints, limbs and fingers
• Slow physical growth before and after birth
• Vision difficulties or hearing problems
• Small head circumference and brain size
• Heart defects and problems with kidneys and bones

Brain and central nervous system problems

Problems with the brain and central nervous system may include:

• Poor coordination or balance
• Intellectual disability, learning disorders and delayed development
• Poor memory
• Trouble with attention and with processing information
• Have trouble following directions and learning how to do simple things.
• Difficulty with reasoning and problem-solving
• Difficulty identifying consequences of choices
• Poor judgment skills
• Jitteriness or hyperactivity
• Have problems eating and sleeping.
• Rapidly changing moods

Social and behavioral issues

Problems in functioning, coping and interacting with others may include:

• Difficulty in school
• Have trouble paying attention and learning in school.
• Trouble getting along with others
• Poor social skills
• Trouble adapting to change or switching from one task to another
• Problems with behavior and impulse control
• Have trouble getting along with others and controlling their behavior.
• Poor concept of time
• Problems staying on task
• Difficulty planning or working toward a goal
• Need medical care all their lives.
• Need special teachers and schools.

A child with fetal alcohol syndrome can struggle in many areas of life without adequate help. Other than their difference in appearance, there are other less obvious problems, mostly affecting the brain. Children with fetal alcohol spectrum usually have slightly lower IQs than other children, with a greater reduction in those whose parents drank more. They have problems with learning and attention and this can lead to antisocial behavior and aggressiveness. As little as one drink a day can lead to an increase in aggressiveness in children aged six to seven. Fetal alcohol spectrum can even lead to Attention Deficit Disorder when the children reach their teens.

Fetal alcohol syndrome diagnosis

Diagnosing fetal alcohol syndrome can be hard because there is no medical test for fetal alcohol syndrome.

To make a diagnosis of fetal alcohol syndrome, your doctor:

• Discusses drinking during pregnancy. If you report the timing and amount of alcohol consumption, your obstetrician or other health care provider can help determine the risk of fetal alcohol syndrome. Although doctors can’t diagnose fetal alcohol syndrome before a baby is born, they can assess the health of the mother and baby during pregnancy.
• Watches for signs and symptoms of fetal alcohol syndrome in your child’s initial weeks, months and years of life. This includes assessing physical appearance and distinguishing features of your baby, such as a low birth weight and a small head and monitoring your child’s physical and brain growth and development.

Your doctor will look at behavioral symptoms, such as attention and coordination. They will ask you if you drank while you were pregnant and if so, how much.

Fetal alcohol syndrome can be difficult to diagnose in childhood because it has similar symptoms to other disorders, such as ADHD (attention deficit and hyperactivity disorder) and Williams syndrome, have some symptoms like fetal alcohol syndrome.

If fetal alcohol syndrome is suspected, your pediatrician may refer your child to a developmental pediatrician, a neurologist or another expert with special training in fetal alcohol syndrome for evaluation and to rule out other disorders with similar signs and symptoms.

Fetal alcohol syndrome treatment

There is no cure for fetal alcohol syndrome. It lasts a lifetime. As there is no treatment other than supportive care for children with fetal alcohol syndrome, the major way of lessening the impact of fetal alcohol syndrome is to not drink while pregnant.

If a child is born with fetal alcohol syndrome, there are many services available to help with any problems they may have. While there may not be a cure for fetal alcohol syndrome, the more help they receive the better. Their treatment involves providing them with good medical and dental care. This includes eyeglasses or hearing aids, if needed. Some behavioral symptoms can be managed with medicine. Children can be placed in special school programs to treat behavior or development issues.

Early intervention services may help reduce some of the effects of fetal alcohol syndrome and may prevent some secondary disabilities. Intervention services may involve:

• A team that includes a special education teacher, a speech therapist, physical and occupational therapists, and a psychologist
• Early intervention to help with walking, talking and social skills
• Special services in school to help with learning and behavioral issues
• Medications to help with some symptoms
• Medical care for health problems, such as vision problems or heart abnormalities
• Addressing alcohol and other substance use problems, if needed
• Vocational and life skills training
• Counseling to benefit parents and the family in dealing with a child’s behavioral problems

If your child is younger than 3 years old, contact your local early intervention system (https://www.cdc.gov/ncbddd/actearly/parents/states.html). Find your state’s early intervention contact information here (https://www.cdc.gov/ncbddd/actearly/parents/states.html).

If your child is 3 years old or older, contact your local public school system (more information here http://www.parentcenterhub.org/ei-overview/). Even if your child is not old enough for kindergarten or enrolled in a public school, call your local elementary school or board of education and ask to speak with someone who can help you have your child evaluated.

Treatment for mothers with alcohol problems

Treating the mother’s alcohol use problem can enable better parenting and prevent future pregnancies from being affected. If you know or suspect you have a problem with alcohol or other substances, ask a medical or mental health professional for advice.

If you’ve given birth to a child with fetal alcohol syndrome, ask about substance abuse counseling and treatment programs that can help you overcome your misuse of alcohol or other substances. Joining a support group or 12-step program such as Alcoholics Anonymous (http://www.aa.org/) also may help.

What is Early Intervention for fetal alcohol syndrome?

Early Intervention

• Is the term used to describe the services and supports that are available to babies and young children with developmental delays and disabilities and their families.
• May include speech therapy, physical therapy, and other types of services based on the needs of the child and family.
• Can have a significant impact on a child’s ability to learn new skills and overcome challenges and can increase success in school and life.
• Programs are available in every state and territory, see each program’s contact information for your state here http://www.parentcenterhub.org/preschoolers/ and here (https://www.cdc.gov/ncbddd/actearly/parents/states.html). These publicly funded programs provide services for free or at reduced cost for any child who is eligible.

How do I find out if my child is eligible for services?

Eligibility for early intervention services is based on an evaluation of your child’s skills and abilities.

If you, your child’s doctor, or other care provider is concerned about your child’s development, ask to be connected with your state or territory’s early intervention program to find out if your child can get services to help. If your doctor is not able to connect you, you can reach out yourself. A doctor’s referral is not necessary.

• If your child is under age 3: Call your state or territory’s early intervention program (https://www.cdc.gov/ncbddd/actearly/parents/states.html) and say: “I have concerns about my child’s development and I would like to have my child evaluated to find out if he/she is eligible for early intervention services.”
• If your child is age 3 or older: http://www.parentcenterhub.org/preschoolers/

Living with fetal alcohol syndrome

The psychological and emotional problems associated with fetal alcohol syndrome can be difficult to manage for the person with the syndrome and for the family.

Most babies born with fetal alcohol syndrome will not have normal brain development. They will need ongoing therapy or special services. The outlook for them depends on how severe their problems are. The best parents can do is get them diagnosed early. This will allow doctors to create specialized plans for their development and education. In addition to early diagnosis, research shows that children also do best if they:

• Are raised in a stable home.
• Are not exposed to violence.
• Receive special education and social services.

Older children and adults with fetal alcohol syndrome can also face challenges. According to the National Institute for Alcohol Abuse and Alcoholism, people with fetal alcohol syndrome or other Fetal Alcohol Spectrum Disorder problems can have trouble with:

• Learning and remembering.
• Paying attention.
• Understanding and following directions.
• Controlling emotions and impulses.
• Communicating and socializing.
• Performing daily life activities, such as bathing, dressing, eating, or telling time.

They are also more likely to have mental health disorders, including:

• ADHD.
• Depression and anxiety.
• Hyperactivity and impulse control.
• Substance abuse disorders.

Remember that no amount of alcohol is safe in pregnancy. Quit drinking if you are trying to get pregnant or if you think you’re pregnant. If you can’t quit drinking by yourself, get help right away.

Family support

Children with fetal alcohol syndrome and their families may benefit from the support of professionals and other families who have experience with this syndrome. Ask your health care provider, social worker or mental health professional for local sources of support for children with fetal alcohol syndrome and their families.

Dealing with behavioral problems

As a parent of a child with fetal alcohol syndrome, you may find the following suggestions helpful in dealing with behavioral problems associated with the syndrome. Learning these skills (sometimes called parent training) can include:

• Recognizing your child’s strengths and limitations
• Implementing daily routines
• Creating and enforcing simple rules and limits
• Keeping things simple by using concrete, specific language
• Using repetition to reinforce learning
• Pointing out and using rewards to reinforce acceptable behavior
• Teaching skills for daily living and social interactions
• Guarding against your child being taken advantage of by others because many children with fetal alcohol syndrome are at risk of this

Early intervention and a stable, nurturing home are important factors in protecting children with fetal alcohol syndrome from some of the secondary disabilities they’re at risk of later in life.

Symbrachydactyly

Symbrachydactyly is a rare congenital hand defect that is characterized by failure of formation of fingers and presence of rudimentary nubbins (short fingers in which bones are missing or are smaller than normal) that include elements of nail plate, bone, and cartilage ¹⁾. Typically, the central digits are absent and the border digits are relatively spared, and syndactyly may be present (Figure 1) ²⁾. The bones, muscles, ligaments and nerves of the hand are usually affected. The roots of the word are from the Greek “syn/sym” (joined), “brachy” (short) and “dactyl” (finger, digit).

Symbrachydactyly occurs in about one out of every 32,000 babies. It affects boys and girls equally.

Most cases of symbrachydactyly happen for no known reason and without any other abnormalities in the child. It isn’t thought to be inherited. In some cases, symbrachydactyly is an accompanying defect in a genetic syndrome called Poland syndrome, in which there is underdevelopment of the chest muscle (hypoplasia or absence of the pectoralis major) on one side of the body ³⁾. In fact, Poland first described symbrachydactyly in 1841 ⁴⁾.

There are different levels of symbrachydactyly:

• The thumb is essentially normal, but the remaining fingers are short and stiff and can be webbed (least severe).
• Only the thumb or the thumb and little finger are present (moderately severe).
• All the fingers are missing, and small skin stumps are located where fingers should have developed (most severe).

Many forms of symbrachydactyly are treated surgically. Initial surgery is usually done when the child is between 6 and 18 months old. Sometimes, a series of additional surgeries need to be performed over a period of years.

Treatment of symbrachydactyly varies from child to child. In some cases, no surgery or only minor skin and soft-tissue corrections are needed.

Figure 1. Symbrachydactyly hand

Footnote: A typical hand with symbrachydactyly.

[Source ⁵⁾ ]

Symbrachydactyly classification

The International Federation of Societies for Surgery of the Hand has recently adopted the Oberg, Manske, and Tonkin (OMT) classification system ⁶⁾, which incorporates current understanding of embryology and molecular biology. Under the previous International Federation of Societies for Surgery of the Hand system, symbrachydactyly was categorized as an undergrowth ⁷⁾; in the OMT system ⁸⁾, symbrachydactyly is categorized as failure of formation of the proximal-distal axis, which can involve the entire upper limb or the hand plate.

Several classifications of symbrachydactyly have been described. Blauth ⁹⁾ refined Müller’s original concepts ¹⁰⁾ into a classification system for symbrachydactyly that included 4 phenotypes:

1. Short finger type
2. Cleft hand type
3. Monodactyly type: absence of digits 2 to 5, with the thumb present
4. Peromelic type: adactyly with rudimentary nubbins.

Yamauchi and Tanabu ¹¹⁾ described a more elaborate classification of 7 types based on the morphological and radiographic bony deficiency, allowing for precise description of skeletal elements of the affected hand and extremity, but not providing guidance for treatment. Foucher ¹²⁾ modified the Blauth classification to make it more useful in this regard, based on a series of 117 patients. The presence of a thumb, the stability of joints, and the patient-specific needs were used to recommend surgical treatment (see Table 1 and Figure 2).

Figure 2. Spectrum of symbrachydactyly

Footnote: The spectrum of symbrachydactyly as classified by Foucher: (a) type I, (b) type IIA, (c) type IIB, (d) type IIC, (e) type IIIA, (f) type IIIB, (g) type IVA, and (h) type IVB.

Note. A description of each type is listed in Table 1 below.

[Source ¹³⁾ ]

Table 1. Foucher’s Symbrachydactyly Classification

Type	Features	Thumb	Ulnar digit	Interventions
I	All bones and digits present, brachydactyly and syndactyly	Normal	Bones present, brachydactyly or syndactyly	Syndactyly release
IIA	≥2 fingers. Normal thumb, hypoplastic fingers	Normal	Hypoplastic, syndactyly	Nonvascularized toe phalanx transfers, ablation, or stabilization
IIB	Functional border digits, variable central nubbins	Normal	Present, variable hypoplasia and stability	Surgery rarely indicated
IIC	“Spoon hand,” thumb conjoined with hypoplastic ulnar digits	Present (± stability)	Hypoplastic, clinodactyly	Variable
IIIA	Monodactyly	Normal	Absent	Vascularized toe-to-hand transfer
IIIB	Monodactyly	Hypoplastic and/or unstable	Absent	Variable, vascularized toe-to-hand transfer, thumb stabilization, thumb lengthening
IVA	Peromelic, wrist mobility	Absent	Absent
IVB	Peromelic, no wrist mobility	Absent	Absent	Surgery not indicated

[Source ¹⁴⁾ ]

Symbrachydactyly causes

The cause of symbrachydactyly is unknown, but vascular dysgenesis during fetal development (“subclavian artery supply disruption sequence”) is a leading hypothesis ¹⁵⁾. Based on this hypothesis, isolated transverse terminal limb deficiencies are associated with interruption of the subclavian artery distal to the internal thoracic artery before a gestational age of 42 days, leading to a failure of outward limb growth and interdigital tissue degeneration. In support of this theory, a study of 8 patients with Poland syndrome showed decreased blood flow velocity in affected limbs, likely from a subclavian malformation ¹⁶⁾.

Based on the current understanding of upper limb development, symbrachydactyly likely arises through disruption of the apical ectodermal ridge of the developing limb bud. The apical ectodermal ridge, a thickening of ectodermal cells at the distal end of the limb bud, directs proximal-distal limb development through a complex cascade of growth factors and genetic signaling, while controlling aspects of mesenchyme cell differentiation ¹⁷⁾. In animal models, disruption of the apical ectodermal ridge and its signaling pathways causes transverse deficiencies, including symbrachydactyly ¹⁸⁾.

Although limb development occurs in a proximal-distal direction, there may be some regenerative capacity of distal limb elements after a partial or complete insult to the apical ectodermal ridge that may result in the characteristic “nubbins” or rudimentary digits seen in symbrachydactyly ¹⁹⁾.

Symbrachydactyly symptoms

Symbrachydactyly symptoms can vary widely. Symbrachydactyly is visible at, or shortly after, birth. Sometimes it is seen on ultrasound before birth. Your child’s fingers will be short and webbed. In severe cases, your child’s fingers will be small stumps of skin and soft tissue. Because of these differences, your child may have trouble using the affected hand.  Normally only one hand is affected. Symptoms include:

• Short fingers in which bones are missing or are smaller than normal (brachydactyly). Sometimes referred to as “nubbins.”
• Missing fingers.
• Fingers that are joined or webbed (cutaneous syndactyly).
• Missing thumb or one that is shorter than usual.
• Short bones in the wrist or arm.
• Muscles, tendons and ligaments can be affected.

Symbrachydactyly diagnosis

Symbrachydactyly is apparent at birth and may also be visible before birth by ultrasound. In most cases, the underlying muscles, nerves, tendons, ligaments and bones of your child’s hand will be affected. Your doctor will use x-rays to look more closely at the underlying structure of your baby’s fingers and determine a course of treatment. If there are any other abnormalities, other x-rays or tests may be needed.

Symbrachydactyly is often confused with a hand disorder called constriction ring syndrome, but the two are different. The main difference between the two is that in symbrachydactyly the underlying structures of the hand, such as the muscles, nerves and bones, are usually malformed, while in constriction ring syndrome they aren’t.

Symbrachydactyly differential diagnosis

Confusion surrounding the definition of symbrachydactyly is due to variability in clinic presentation, including the amount of hypoplasia of the central digits, affected hand size, and the function of border digits. The term symbrachydactyly has been used to describe hand malformations that overlap with transverse deficiency, central deficiency, brachymetacarpia, brachyphalangism, and hypodactyly ²⁰⁾. Symbrachydactyly was previously called “atypical cleft hand” due to morphological similarities with central deficiency ²¹⁾, but this terminology has been abandoned ²²⁾; central deficiency is an autosomal dominant condition in which the central rays are absent; it is usually bilateral and often associated with cleft feet. Other conditions in the differential diagnosis of symbrachydactyly include Apert syndrome, amniotic constriction bands, ulnar longitudinal deficiency, and hypodactyly (Table 2) ²³⁾.

Table 2. Differential diagnosis of Symbrachydactyly

	Symbrachydactyly	Apert syndrome	Amniotic constriction band	Central deficiency	Ulnar longitudinal deficiency	Hypodactyly
Origin	Sporadic	Mutation, FGFR2	Sporadic	Heritable, multiple loci	Generally sporadic, occasionally syndromic	Sporadic
Upper extremities	Unilateral	Bilateral, complex syndactyly	Usually bilateral, unilateral is rare	Generally bilateral	Unilateral	Unilateral
Lower extremities	Not affected	Affected	Affected (constriction bands and talipes equinovarus)	Affected	Not affected	Not affected
Thumb involvement	Least likely digit to be involved (peromelic and monodactylous forms)	Commonly involved in complex syndactyly	Equally likely to be involved as other digits	First web space commonly shallow/narrow. Thumb rarely suppressed	Least likely digit to be involved, but can be affected	Least likely digit to be involved, but can be affected
Shape of hand defect	U-shaped cleft	Cup like	Amputations common distal to bands	V-shaped cleft	Missing ulnar-sided structures, smooth contours on hand	Missing terminal elements only, deficiency may be more severe at ulnar digits
Unique features	Rudimentary nubbins with ectodermal tissue. Metacarpals present	Facial features (craniosynostosis, acrocephaly)	Visible scarring/depression from amniotic band	Absent metacarpals	Proximal structures (ie, elbow) more likely affected than wrist	Multiple shortened digits without terminal ectodermal elements

Symbrachydactyly treatment

Specific treatment for symbrachydactyly will be determined by your child’s doctor based on:

• Your child’s age, overall health and medical history.
• Your child’s tolerance for specific procedures or therapies.
• Expectations for the course of the disease.
• Your opinion or preference

The goals of treating congenital hand differences are to maximize function, normalize appearance, and help the child and family accept the difference to the extent that it cannot be “normalized” ²⁴⁾. Selection of a specific treatment for symbrachydactyly depends on the clinical and radiological findings, the ability of the child to meet developmental milestones and perform activities of daily living, and the expectations of the child and family regarding the appearance of the hand. Treatment is grounded in the framework of realistic functional goals, with a reasonable expectation that the treatment can achieve that goal.

Treatment may include (alone or in combination):

• Corrective Surgeries
  • Surgery to divide webbed fingers
  • Bone transfer (phalangeal transfer): One bone from each toe is removed and placed into each of the short fingers. This lengthens the fingers and makes gripping objects easier. Removing bones from the toes will not cause problems with walking.
  • Distraction: A metal rod is placed in the transferred bones and slowly expanded to make the bones longer.
• Occupational therapy
• Physical therapy
• Prosthesis
  • An artificial body part that can be used for cosmetic or functional purposes.

Nonoperative management

Function is classified according to the World Health Organization International Classification of Functioning and Disability ²⁵⁾. Activity, participation, and quality of life may be very close to normal for children with unilateral hand absence ²⁶⁾. Often the biggest challenge to the child and family is the psychological burden of appearing different to others ²⁷⁾.

Nonoperative interventions, such as therapy, prostheses, and orthotics, have been used to treat children with symbrachydactyly. An occupational therapist can help children with unilateral malformations master activities of daily life while increasing self-esteem and gaining independence ²⁸⁾.

Because they cannot provide sensation, prostheses have limited applications for children with unilateral conditions, especially when the affected side has wrist motion and/or at least one sensate digit that can assist the contralateral hand with bimanual activities. Opposition paddles or partial hand prostheses may be helpful for patients with a stable monodactyly because they provide a surface to pinch against (Figure 3). Customized passive hand prostheses may provide relief from unwelcome questions and comments. As technology improves so that components can be made smaller, less expensive, and more durable, myoelectric partial hand prostheses may become useful to children with symbrachydactyly.

Peer groups and hand camps may improve the child’s quality of life more than medical or surgical treatment ²⁹⁾. Camps exist for children with various chronic illnesses and congenital conditions; these have been shown to provide short-term psychosocial benefits, including improved social interaction and acceptance ³⁰⁾. Camps for children with congenital hand differences include Camp Winning Hands in Livermore, California (https://www.shrinersinternational.org) and Hand Camp in Meridian, Texas (https://scottishriteforchildren.org/plan-your-visit/therapeutic-sports-recreation/camps).

Figure 3. A patient with symbrachydactyly wearing an opposition paddle

Symbrachydactyly surgery

Surgical treatments are categorized by the specific aspect of symbrachydactyly that the treatment addresses: syndactyly and web contracture, brachydactyly and digit instability, and lack of opposition.

If your child has a more serious case, he may need to have bones transferred, usually from the toes, to add length to the affected fingers. In some cases, a toe or multiple toes are transplanted to the affected hand (a process called toe transfer or toe-to-hand transfer) so that your child will eventually be able to pinch, pick up and hold objects.

Complications right after surgery are uncommon and usually minor. But medium- to longer-term complications can include:

• infection
• poor bone healing
• stiff knuckle joints
• finger dislocation

After surgery, your child is usually placed in an above-elbow cast for three weeks to help immobilize and protect the hand. Once the cast is removed, a splint that slides in between the fingers and keeps them apart is used for an additional six weeks. During this time, your child’s doctor may recommend occupational or physical therapy to help reduce scarring, stiffness and swelling and improve function.

Doctors will want to see your child for follow-up visits to ensure that healing is proceeding well and function has returned. In some cases, follow-up will continue for years to evaluate whether additional surgery is needed to improve the function or appearance of your child’s hand.

Syndactyly and web contracture

Syndactyly and web contractures are treated to improve independent digital function, grasp span, and appearance. For incomplete simple syndactyly of the digits, 2-fold or 4-fold Z-plasty is usually sufficient ³¹⁾. Options for deepening the first web space include multiple Z-plasties, local rotational flaps, and more complex advancement techniques ³²⁾. Release of the first web space in symbrachydactyly can be more challenging than similar releases done for other diagnoses due to a lack of local skin available ³³⁾.

Brachydactyly and digit instability

Nonvascularized free toe phalanx transfers

This operation is intended to augment the length and stability of the fingers to improve prehension and appearance. It has been advocated for short metacarpals or phalanges with an adequate distal soft-tissue envelope to receive the transferred phalanx; toe proximal phalanges must be available for transfer ³⁴⁾. The literature reveals variable results, with longer term follow-up showing more disappointing outcomes.

The technique includes preserving the volar plate, collateral ligaments, physis, and periosteum of the transferred phalanx, as described by Goldberg ³⁵⁾. In that series of 15 patients, the authors found that physes were more likely to remain radiographically open in children who were younger at the time of the transfer ³⁶⁾.

Buck-Gramcko ³⁷⁾ reported similar outcomes in 97 extraperiosteal nonvascularized proximal toe phalanx transfers in 57 children, and Radocha ³⁸⁾ reported that the preservation of the periosteum contributed to the growth of the transferred segment in children younger than 12 months at the time of surgery.

More recently, however, Cavallo ³⁹⁾ studied 64 nonvascularized toe phalanx transfers in 22 children, 18 with symbrachydactyly, and concluded that little longitudinal growth occurred but transverse growth did occur, and contributed stability to the digits. In 11 cases, the transfer was unstable; this complication was most common in patients with symbrachydactyly.

Tonkin ⁴⁰⁾ reported on 10 children treated with nonvascularized toe phalanx transfers, with a mean follow-up of 7 years. Function testing showed that 5 could use their digit for complex activities, 2 for simple tasks, and 3 for assisting the other hand. Parents reported satisfaction with appearance of the hand and feet, but felt there was no improvement in the hand’s function. Most recently, Garagnani ⁴¹⁾ studied 40 children with a mean follow-up of 10 years, and found ubiquitous donor site morbidity that increased with growth, along with a high rate of emotional problems with foot appearance and functional problems with footwear.

None of these studies followed children to skeletal maturity and few offered thorough assessments of the function and appearance of the hand following surgery, making evaluation of this procedure difficult. Complete resorption of the transferred phalanx has been observed, as might be expected with a terminal bone graft, and claims of advantages of performing this operation early have not held up. Furthermore, claims of growth of the transferred phalanx are often based on radiographic patency of the physis, but animal studies have shown that radiolucency does not necessarily indicate that a physis is growing ⁴²⁾. If surgery is postponed until the child is older they can participate in the decision making, the phalanx is larger, and there is less growth potential to lose.

This operation may be useful in type IIA symbrachydactyly, when the base of the proximal phalanx is present along with a generous soft-tissue envelope. The cartilage at the base of the transferred phalanx can be debrided allowing bony healing between the ossific nucleus and the phalanx, reducing the likelihood of instability. When considering this operation, the surgeon should counsel parents and patients to adjust their expectations for cosmetic and functional outcomes, including foot appearance ⁴³⁾.

Distraction lengthening

Lengthening a bone by distraction osteogenesis with or without secondary intercalary bone grafting is potentially useful for the treatment of short fingers in symbrachydactyly, but the indications for lengthening are unclear ⁴⁴⁾. This treatment rarely normalizes appearance and is fraught with complications. The literature shows mixed results with little information to indicate whether this procedure improves function and appearance.

Hulsbergen-Kruger’s ⁴⁵⁾ series of 3 patients with symbrachydactyly indicated that attempts to lengthen hypoplastic bones, including transferred toe proximal phalanges, resulted in pseudarthroses, infections, and resorption with no reported improvement in function. Foucher20 reviewed results of distraction lengthening in 41 patients (22 with symbrachydactyly) and reported an average gain of 2.3 cm over 4 months. Complications included infection, nonunion, or fracture in 32%. Miyawaki ⁴⁶⁾ reported 4 successful cases of metacarpal lengthening in patients with types IIA, IIB, and IIIA, noting improved pinch strength with no major complications; Matsuno et al ⁴⁷⁾ have reported angulation of the lengthened bones, with unsatisfactory appearance. Heo ⁴⁸⁾ reported a series of 24 metacarpal and 27 phalangeal lengthening procedures with a 31% complication rate, including nonunion, fracture, premature consolidation, angulation, and hardware failure.

Seitz ⁴⁹⁾ has reported a large series reflecting his long-term experience with distraction lengthening in the arm, forearm, and hand for children with a wide range of conditions. He acknowledges that this treatment is complex and arduous and has a high complication rate (50% minor, 9% major) but reports that in most cases increased length is achieved and the family and child are satisfied ⁵⁰⁾.

Given the high rates of complications reported for distraction lengthening and the paucity of evidence to support significant functional gains, we rarely perform this procedure and do not advocate it for symbrachydactyly.

Free vascularized toe-to-hand transfer

Although toe-to-hand transfer is well accepted for the treatment of traumatic amputations in adults and children, its indications for reconstruction of congenital malformations remain more nuanced.

In 1988, Lister ⁵¹⁾ described 12 toe-to-hand transfers in children with various congenital hand differences, including 3 cases of symbrachydactyly, and noted unique neurovascular anatomic variations in each patient. Others have reinforced that there is a wide variation in the neurovascular structures in symbrachydactyly ⁵²⁾. In 2001, Foucher ⁵³⁾ reported on 51 toe transfers in 45 patients with symbrachydactyly. Transfers to types IIIA and IIIB were the most common, followed by type IVA. In children with type IIIB, a combination of toe transfers to finger positions with vascularized epiphysis and nonvascularized toe phalanx transfer to the thumb was done. They found no functional problems with donor feet. At 5-year follow-up, range of motion (ROM) was adequate, and most participants reported that they used the affected hand in daily activities.

In 2004, Richardson ⁵⁴⁾ described the results of 18 free toe transfers in 13 patients with symbrachydactyly. The results of a bimanual hand function questionnaire indicated that 61% could lift a cup, 54% could button, 38% could cut paper, and 30% could use a knife and fork; 85% of parents were happy with the appearance of the hand and 77% were happy with the function of the hand. Because of diverse vascular anatomy, the authors recommended obtaining an angiogram preoperatively.

Schenker ⁵⁵⁾ evaluated grip function after free toe transfer in children with hypoplastic digits, finding that the participants could use the transferred digit to lift a small object with a precision grip, but only one-third modulated their grip in proportion to the load being grasped. They found increased forces on the fingertips of transplanted digits during grasp, and concluded that this was due to misalignment of the finger during the grasp ⁵⁶⁾.

Bellew ⁵⁷⁾ reported 10-year follow-up of 33 children (21 with symbrachydactyly) who had toe-to-hand transfers focusing on psychological outcomes. Children and their parents reported psychological well-being, satisfaction with the appearance of the transferred digit and the donor site, and positive reactions from others, and felt that the transferred digit served a functional role in daily activities.

Kaplan ⁵⁸⁾ administered the Pediatric Outcome Data Collection Instrument (PODCI) to 15 children who had toe-to-hand transfers and found that scores for self-reports of upper extremity function and transfer/mobility, and parent reports of global function, upper extremity function, and sports/physical function, were lower than normative scores (they did not compare postoperative with preoperative scores). They also found that parents underestimated sports/physical function and happiness compared with the patient reports; this has been shown for other congenital conditions as well ⁵⁹⁾.

Anatomical variation in vascular structures engenders concern about potential effect of these anomalies on the viability of the vascular anastomoses and survival of the transferred toe. A review of toe-to-hand transfers in congenital hand differences ⁶⁰⁾, however, found an average transplant survival rate of more than 96%. Other issues include unpredictable range of motion in the transferred digit; as some surgeons have noted, the vascularized toe transfer often results in a sensate post for prehension by another digit ⁶¹⁾.

Jones ⁶²⁾ proposed a morphologic framework of indications for vascularized toe transfer for thumb and finger reconstruction in congenital conditions, including “complete absence of the thumb and all four fingers” and finger reconstruction when there is “absence of all four fingers but with normal thumb function,” which correspond to types IIIA and IVA symbrachydactyly. However, the indications for toe-to-hand transfers are still being established for unilateral symbrachydactyly. Creating opportunities for pinch and grip are important but should be weighed against the risks of surgery, and parental expectations must be aligned with realistic outcomes. Further research is needed to determine whether this operation improves function from baseline and to distinguish any postoperative functional changes from normal child development.

Future directions

The advent of composite tissue transplantation has led to the reality of hand transplantation for adults with traumatic hand loss. There are many risks to this operation, including the long-term need for immunosuppressive medication; in addition, psychological counseling is imperative beforehand ⁶³⁾. These challenges, along with the uncertainty of growth potential, contraindicate this operation in children with unilateral hand conditions. Tissue engineering has the potential to address the challenge of limited tissue availability for reconstructing the congenitally malformed hand. Engineering de novo tendons or augmenting tendon regeneration has the potential to overcome the lack of suitable donor tendons for use in the hand ⁶⁴⁾. The creation of composite tissues could someday mean that patient-derived digits could be grown ex vivo and transplanted ⁶⁵⁾.

Symbrachydactyly prognosis

Symbrachydactyl patients often have mild limitations in daily activities.

Symbrachydactyl prognosis greatly depends on:

• The extent of the disease.
• The response to therapy.
• Age and overall health of the child.
• Your child’s tolerance of specific procedures or therapies.
• New developments in treatment.

Surgery can be very successful in helping the use and appearance of the hand. If your child’s case is severe, they may need additional reconstructive surgery or multiple surgeries to achieve greater function and improve their hand’s appearance. But to some extent, the hand will always look different and function differently. As your child grows, they may use prosthetics for some sports and activities.

Your child may need to be followed for a number of months or years to:

• ensure that the healing has gone well
• check that function has returned to your child’s hand
• determine whether additional surgery is needed to improve the function or appearance of the hand as your child grows (additional procedures often needed to deepen the web space between fingers using skin grafts).